Pyrimidines

ABSTRACT

The present invention encompasses compounds of general formulae (1 a ) and (1 b ) 
                         
wherein
     the groups R 1  to R 5 , A, Q, m, n, p and q are defined as in claim  1 , which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and their use as medicaments.

The present invention relates to new pyrimidines of general formulae(1a) and (1b)

wherein the groups R¹ to R⁵, A, Q, m, n, p and q have the meanings givenin the claims and specification, the isomers thereof, processes forpreparing these pyrimidines and their use as medicaments.

BACKGROUND TO THE INVENTION

Tumour cells that acquire the properties for invasion andmetastasisation require specific survival signals. These signals allowthem to overcome special apoptosis mechanisms (anoikis) which aretriggered, inter alia, by the loss of cell adhesion. In this process,focal adhesion kinase (FAK/PTK2) is one of the essential signalmolecules which on the one hand controls cell-matrix interactionsthrough so-called local adhesions' and on the other hand imparts anoikisresistance. Interference with these mechanisms by inhibiting PTK2 maylead to the apoptotic cell death of tumour cells and limit the invasiveand metastasising growth of tumours. In addition, focal adhesion kinasehas major significance for the growth, migration and survival oftumour-associated endothelial cells. An anti-angiogenic activity maytherefore also be achieved by inhibiting PTK2.

Pyrimidines are generally known as inhibitors of kinases. Thus, forexample, pyrimidines are described as aurora-kinase inhibitors inInternational Patent Application WO 2008/038011, these pyridines having,as substituents, an oxymethylpiperidinyl group in the 4 position andfluorine in the 5 position.

The aim of the present invention is to indicate new pyrimidines asactive substances which can be used for the prevention and/or treatmentof diseases characterised by excessive or abnormal cell proliferation. Afurther aim of the present invention is to indicate pyrimidines whichhave an inhibitory effect on the enzyme PTK2 in vitro and/or in vivo andhave suitable pharmacological and/or pharmacokinetic properties toenable them to be used as medicaments. These properties include interalia a selective inhibitory effect on PTK2 in relation to other knowncell cycle and signal kinases.

DETAILED DESCRIPTION OF THE INVENTION

It has now been found that, surprisingly, compounds of general formulae(1a) and (1b), wherein the groups R¹ to R⁵, A, Q, m, n, p and q have themeanings given hereinafter act as inhibitors of specifictyrosine-kinases. Thus the compounds according to the invention may beused for example for the treatment of diseases connected to the activityof specific tyrosine-kinases and characterised by excessive or abnormalcell proliferation.

The present invention relates to compounds of general formulae (1a) and(1b)

wherein

-   A denotes a group, optionally substituted by one or more, identical    or different R², selected from among C₃₋₁₀cycloalkyl, 3-8 membered    heterocycloalkyl, C₆₋₁₅aryl and 5-12-membered heteroaryl;-   Q denotes a group, optionally substituted by one or more, identical    or different R⁴, selected from among phenyl and 5-6 membered    heteroaryl;-   R¹ denotes a group selected from among halogen, —OR^(c), —OCF₃,    —SR^(c), —NR^(c)R^(c), —CF₃, —CN, —OCN, —SCN, —NO, —NO₂, C₁₋₃alkyl,    C₁₋₃haloalkyl and C₁₋₃haloalkyloxy;-   R², R⁴ and R⁵ each independently of one another denote hydrogen or a    group selected from among R^(a), R^(b) and R^(a) substituted by one    or more, identical or different R^(c) and/or R^(b);-   R³ denotes a group selected from among —OS(O)R^(c), —OS(O)₂R^(c),    —OS(O)₂OR^(c), —OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c), —OC(O)R^(c),    —OC(O)OR^(c), —OC(O)SR^(c), —OC(O)NR^(c)R^(c), —SC(O)R^(c),    —SC(O)OR^(c), —SC(O)NR^(c)R^(c), —N(R^(g))C(O)R^(c), —N[C(O)R^(c)]₂,    —N(OR^(g))C(O)R^(c), —N[C(O)R^(c)]NR^(c)R^(c), —N(R^(g))S(O)R^(c),    —N(R^(g))S(O)OR^(c), —N(R^(g))S(O)₂R^(c), —N[S(O)₂R^(c)]₂,    —N(R^(g))S(O)₂OR^(c), —N(R^(g))S(O)₂NR^(c)R^(c),    —N(R^(g))[S(O)₂]₂R^(c), —N(R^(g))C(O)OR^(c), —N(R^(g))C(O)SR^(c),    —N(R^(g))C(O)NR^(c)R^(c), —N(R^(g))C(O)NR^(g)NR^(c)R^(c),    —[N(R^(g))C(O)]₂R^(c), —N(R^(g))[C(O)]₂R^(c), —N{[C(O)]₂R^(c)}₂,    —N(R^(g))[C(O)]₂OR^(c), —N(R^(g))[C(O)]₂NR^(c)R^(c),    —N{[C(O)]₂OR^(c)}₂, —N{[C(O)]₂NR^(c)R^(c)}₂ and    —[N(R^(g))C(O)]₂OR^(c);-   each R^(a) is independently selected from among C₁₋₆alkyl,    C₃₋₁₀cycloalkyl, C₄₋₁₆ cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl,    2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14    membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18    membered heteroarylalkyl;-   each R^(b) is a suitable group and each is independently selected    from among ═O, —OR^(c), C₁₋₃haloalkyloxy, —OCF₃, ═S, —SR^(c),    ═NR^(c), ═NOR^(c), ═NNR^(c)R^(c), ═NN(R^(g))C(O)NR^(c)R^(c),    —NR^(c)R^(c), —ONR^(c)R^(c), —N(OR^(c))R^(c), —N(R^(g))NR^(c)R^(c),    halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃,    —S(O)R^(c), —S(O)OR^(c), —S(O)₂R^(c), —S(O)₂OR^(c),    —S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(c), —OS(O)₂R^(c),    —OS(O)₂OR^(c), —OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c), —C(O)R^(c),    —C(O)OR^(c), —C(O)SR^(c), —C(O)NR^(c)R^(c),    —C(O)N(R^(g))NR^(c)R^(c), —C(O)N(R^(g))OR^(c),    —C(NR^(g))NR^(c)R^(c), —C(NOH)R^(c), —C(NOH)NR^(c)R^(c),    —OC(O)R^(c), —OC(O)OR^(c), —OC(O)SR^(c), —OC(O)NR^(c)R^(c),    —OC(NR^(g))NR^(c)R^(c), —SC(O)R^(c), —SC(O)OR^(c),    —SC(O)NR^(c)R^(c), —SC(NR^(g))NR^(c)R^(c), —N(R^(g))C(O)R^(c),    —N[C(O)R^(c)]₂, —N(OR^(g))C(O)R^(c), —N(R^(g))C(NR^(g))R^(c),    —N(R^(g))N(R^(g))C(O)R^(c), —N[C(O)R^(c)]R^(c)R^(c),    —N(R^(g))C(S)R^(c), —N(R^(g))S(O)R^(c), —N(R^(g))S(O)OR^(c),    —N(R^(g))S(O)₂R^(c), —N[S(O)₂R^(c)]₂, —N(R^(g))S(O)₂OR^(c),    —N(R^(g))S(O)₂NR^(c)R^(c), —N(R^(g))[S(O)₂]₂R^(c),    —N(R^(g))C(O)OR^(c), —N(R^(g))C(O)SR^(c), —N(R^(g))C(O)NR^(c)R^(c),    —N(R^(g))C(O)NR^(g)NR^(c)R^(c), —N(R^(g))N(R^(g))C(O)NR^(c)R^(c),    —N(R^(g))C(S)NR^(c)R^(c), —[N(R^(g))C(O)]₂R^(c),    —N(R^(g))[C(O)]₂R^(c), —N{[C(O)]₂R^(c)}₂, —N(R^(g))[C(O)]₂OR^(c),    —N(R^(g))[C(O)]₂NR^(c)R^(c), —N{[C(O)]₂OR^(c)}₂,    —N{[C(O)]₂NR^(c)R^(c)}₂, —[N(R^(g))C(O)]₂OR^(c),    —N(R^(g))C(NR^(g))OR^(c), —N(R^(g))C(NOH)R^(c),    —N(R^(g))C(NR^(g))SR^(c) and —N(R^(g))C(NR^(g))NR^(c)R^(c);-   each R^(c) independently denotes hydrogen or a group optionally    substituted by one or more, identical or different R^(d) and/or    R^(e) selected from among C₁₋₆alkyl, C₃₋₁₀cycloalkyl,    C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6 membered    heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered    heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 membered    heteroarylalkyl;-   each R^(d) is a suitable group and each is independently selected    from among ═O, —OR^(e), C₁₋₃haloalkyloxy, —OCF₃, ═S, —SR^(e),    ═NR^(e), ═NOR^(e), ═NNR^(e)R^(e), ═NN(R^(g))C(O)NR^(e)R^(e),    —NR^(e)R^(e), —ONR^(e)R^(e), —N(R^(g))NR^(e)R^(e), halogen, —CF₃,    —CN, —NC, —OCN, —SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)R^(e), —S(O)OR^(e),    —S(O)₂R^(e), —S(O)₂OR^(e), —S(O)NR^(e)R^(e), —S(O)₂NR^(e)R^(e),    —OS(O)R^(e), —OS(O)₂R^(e), —OS(O)₂OR^(e), —OS(O)NR^(e)R^(e),    —OS(O)₂NR^(e)R^(e), —C(O)R^(e), —C(O)OR^(e), —C(O)SR^(e),    —C(O)NR^(e)R^(e), —C(O)N(R^(g))NR^(e)R^(e), —C(O)N(R^(g))OR^(e),    —C(NR^(g))NR^(e)R^(e), —C(NOH)R^(e), —C(NOH)NR^(e)R^(e),    —OC(O)R^(e), —OC(O)OR^(e), —OC(O)SR^(e), —OC(O)NR^(e)R^(e),    —OC(NR^(g))NR^(e)R^(e), —SC(O)R^(e), —SC(O)OR^(e),    —SC(O)NR^(e)R^(e), —SC(NR^(g))NR^(e)R^(e), —N(R^(g))C(O)R^(e),    —N[C(O)R^(e)]₂, —N(OR^(g))C(O)R^(e), —N(R^(g))C(NR^(g))R^(e),    —N(R^(g))N(R^(g))C(O)R^(e), —N[C(O)R^(e)]NR^(e)R^(e),    —N(R^(g))C(S)R^(e), —N(R^(g))S(O)R^(e), —N(R^(g))S(O)OR^(e),    —N(R^(g))S(O)₂R^(e), —N[S(O)₂R^(e)]₂, —N(R^(g))S(O)₂OR^(e),    —N(R^(g))S(O)₂NR^(e)R^(e), —N(R^(g))[S(O)₂]₂R^(e),    —N(R^(g))C(O)OR^(e), —N(R^(g))C(O)SR^(e), —N(R^(g))C(O)NR^(e)R^(e),    —N(R^(g))C(O)NR^(g)NR^(e)R^(e), —N(R^(g))N(R^(g))C(O)NR^(e)R^(e),    —N(R^(g))C(S)NR^(e)R^(e), —[N(R^(g))C(O)]₂R^(e),    —N(R^(g))[C(O)]₂R^(e), —N{[C(O)]₂R^(e)}₂, —N(R^(g))[C(O)]₂OR^(e),    —N(R^(g))[C(O)]₂NR^(e)R^(e), —N{[C(O)]₂OR^(e)}₂,    —N{[C(O)]₂NR^(e)R^(e)}₂, —[N(R^(g))C(O)]₂OR^(e),    —N(R^(g))C(NR^(g))OR^(e), —N(R^(g))C(NOH)R^(e),    —N(R^(g))C(NR^(g))SR^(e) and —N(R^(g))C(NR^(g))NR^(e)R^(e);-   each R^(e) independently denotes hydrogen or a group optionally    substituted by one or more, identical or different R^(f) and/or    R^(g) selected from among C₁₋₆alkyl, C₃₋₈cycloalkyl,    C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6 membered    heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered    heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 membered    heteroarylalkyl;-   each R^(f) is a suitable group and each is independently selected    from among halogen and —CF₃;-   each R^(g) independently denotes hydrogen, C₁₋₆alkyl,    C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6    membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered    heterocycloalkyl, 5-12 membered heteroaryl or 6-18 membered    heteroarylalkyl;-   m and p independently of one another denote 0, 1, 2 or 3 and-   n and q denote 0, 1, 2 or 3;-   optionally in the form of the tautomers, the racemates, the    enantiomers, the diastereomers and the mixtures thereof, and    optionally the salts thereof, particularly the pharmacologically    acceptable acid addition salts thereof.

In a preferred embodiment the present invention relates to compounds ofgeneral formula (1a),

wherein

-   R¹, R², R³, R⁴, A, Q, n and m are as hereinbefore defined.

In another preferred embodiment (A1) the present invention relates tocompounds of general formula (1a), wherein

-   n is 1.

In another preferred embodiment (A2) the present invention relates tocompounds of general formula (1a), wherein

the group R³ and the group

assume a trans configuration with respect to the ring system to whichthey bind.

In another preferred embodiment (B1) the present invention relates tocompounds of general formula (1a), wherein

-   Q is phenyl and-   R⁴ and m are as hereinbefore defined.

In another preferred embodiment (B2) the present invention relates tocompounds of general formula (1a), wherein

-   m is 0.

In another preferred embodiment the present invention relates tocompounds of general formula (1b),

wherein

-   R¹, R², R³, R⁵, A, p and q are as hereinbefore defined.

In another preferred embodiment (A3) the present invention relates tocompounds of general formula (1b), wherein

-   q is equal to 1 or 2.

In another preferred embodiment (A4) the present invention relates tocompounds of general formula (1b), wherein

the group R³ and the group

assume a trans configuration with respect to the ring system to whichthey bind.

In another preferred embodiment (B3) the present invention relates tocompounds of general formula (1b), wherein

-   p is equal to 0.

In another preferred embodiment (C1) the present invention relates tocompounds of general formulae (1a) and (1b), wherein

-   R¹ is a group selected from among halogen, —CF₃, —CN, —C₁₋₃alkyl and    C₁₋₃haloalkyl.

In another preferred embodiment (C2) the present invention relates tocompounds of general formulae (1a) and (1b), wherein

-   R¹ is a group selected from among halogen and —CF₃.

In another preferred embodiment (C3) the present invention relates tocompounds of general formulae (1a) and (1b), wherein

-   R¹ denotes —CF₃.

In another preferred embodiment (C4) the present invention relates tocompounds of general formulae (1a) and (1b), wherein

-   R¹ denotes chlorine.

In another preferred embodiment (D1) the present invention relates tocompounds of general formulae (1a) and (1b), wherein

-   R³ is a group selected from among —N(R^(g))C(O)R^(c),    —N[C(O)R^(c)]₂, —N(OR^(g))C(O)R^(c), —N[C(O)R^(c)]NR^(c)R^(c),    —N(R^(g))S(O)R^(c), —N(R^(g))S(O)OR^(c), —N(R^(g))S(O)₂R^(c),    —N[S(O)₂R^(c)]₂, —N(R^(g))S(O)₂OR^(c), —N(R^(g))S(O)₂NR^(c)R^(c),    —N(R^(g))[S(O)₂]₂R^(c), —N(R^(g))C(O)OR^(c), —N(R^(g))C(O)SR^(c),    —N(R^(g))C(O)NR^(c)R^(c), —N(R^(g))C(O)NR^(g)NR^(c)R^(c),    —[N(R^(g))C(O)]₂R^(c), —N(R^(g))[C(O)]₂R^(c), —N{[C(O)]₂R^(c)}₂,    —N(R^(g))[C(O)]₂OR^(c), —N(R^(g))[C(O)]₂NR^(c)R^(c),    —N{[C(O)]₂OR^(c)}₂, —N{[C(O)]₂NR^(c)R^(c)}₂, and    —[N(R^(g))C(O)]₂OR^(c) and-   R^(c) and R^(g) are as hereinbefore defined.

In another preferred embodiment (D2) the present invention relates tocompounds of general formulae (1a) and (1b), wherein

-   R³ is selected from among —N(R^(g))C(O)R^(c), —N(OR^(g))C(O)R^(c),    —N(R^(g))S(O)₂R^(c), —N(R^(g))C(O)OR^(c) and    —N(R^(g))C(O)NR^(c)R^(c) and-   R^(c) and R^(g) are as hereinbefore defined.

In another preferred embodiment (D3) the present invention relates tocompounds of general formulae (1a) and (1b), wherein

-   R³ is selected from among —N(R^(g))C(O)R^(c), —N(R^(g))S(O)₂R^(c)    and —N(R^(g))C(O)OR^(c) and-   R^(c) and R^(g) are as hereinbefore defined.

In another preferred embodiment (D4) the present invention relates tocompounds of general formulae (1a) and (1b), wherein

-   R³ is selected from among —N(R^(g))C(O)R^(c1) and    —N(R^(g))S(O)₂R^(c1);-   R^(c1) corresponds to the group R^(c) and-   R^(c) and R^(g) are as hereinbefore defined.

In another preferred embodiment (D5) the present invention relates tocompounds of general formulae (1a) and (1b), wherein

-   R³ is selected from among —NHC(O)R^(c1), —N(C₁₋₄alkyl)C(O)R^(c1),    —NHS(O)₂R^(c1) and —N(C₁₋₄alkyl)S(O)₂R^(c1);-   R^(c1) corresponds to the group R^(c) and-   R^(c) is as hereinbefore defined.

In another preferred embodiment (D6) the present invention relates tocompounds of general formulae (1a) and (1b), wherein

-   R³ is selected from among —NHC(O)R^(c1), —N(Me)C(O)R^(c1),    —N(Et)C(O)R^(c1), —N(iPr)C(O)R^(c1), —N(nPr)C(O)R^(c1),    —NHS(O)₂R^(c1), —N(Me)S(O)₂R^(c1), —N(Et)S(O)₂R^(c1),    —N(iPr)S(O)₂R^(c1) and —N(nPr)S(O)₂R^(c1);-   R^(c1) corresponds to the group R^(c) and-   R^(c) is as hereinbefore defined.

In other preferred embodiments (D7)(D8)(D9) the present inventionrelates to compounds of the preferred embodiments (D4) and/or (D5)and/or (D6), wherein

-   R^(c1) is selected from among C₁₋₄alkyl, C₁₋₄haloalkyl,    C₃₋₅cycloalkyl, C₁₋₄alkoxymethyl, (C₁₋₄alkyl)NH—CH₂— and    (C₁₋₄alkyl)₂N—CH₂—.

In other preferred embodiments (D10)(D11)(D12) the present inventionrelates to compounds of the preferred embodiments (D4) and/or (D5)and/or (D6), wherein

-   R^(c1) is selected from among methyl and ethyl.

In another preferred embodiment (D13) the present invention relates tocompounds of general formulae (1a) and (1b), wherein

-   R³ denotes —N(Me)S(O)₂Me.

In another preferred embodiment (E1) the present invention relates tocompounds of general formulae (1a) and (1b), wherein

-   the group

-   denotes

-   R⁶ and R⁷ are defined as R² hereinbefore,-   r is equal to 1 or 2 and-   A is as hereinbefore defined.

In another preferred embodiment (E2) the present invention relates tocompounds of general formulae (1a) and (1b), wherein

-   A is a group selected from among phenyl and 5-10 membered heteroaryl    and-   R⁶, R⁷ and r are as hereinbefore defined.

In another preferred embodiment (E3) the present invention relates tocompounds of general formulae (1a) and (1b), wherein

-   A is phenyl and-   R⁶, R⁷ and r are as hereinbefore defined.

In another preferred embodiment (E4) the present invention relates tocompounds of general formulae (1a) and (1b), wherein

-   A is a phenyl;-   r has the value 1 or 2;-   each R⁷ is independently selected from among halogen, C₁₋₆alkyl and    C₁₋₆alkoxy and-   R⁶ is as hereinbefore defined.

In another preferred embodiment (E5) the present invention relates tocompounds of general formulae (1a) and (1b), wherein

-   A together with R⁶ and the r substituents R⁷ has the partial    structure

-   R^(7a) and R^(7c) each independently denote C₁₋₆alkoxy;-   R^(7b) is selected from among halogen and C₁₋₆alkyl and-   R⁶ is as hereinbefore defined.

In another preferred embodiment (E6) the present invention relates tocompounds of general formulae (1a) and (1b), wherein

-   A together with R⁶ and the r substituents R⁷ has the partial    structure

-   R^(7a) and R^(7c) each independently denote methoxy;-   R^(7b) is selected from among fluorine, chlorine, methyl and ethyl    and-   R⁶ is as hereinbefore defined.

In another preferred embodiment (E7) the present invention relates tocompounds of general formulae (1a) and (1b), wherein

-   A together with R⁶ and the r substituents R⁷ has the partial    structure

-   R^(7d) and R^(7e) each independently of one another denote    C₁₋₆alkoxy;-   R^(7f) is selected from among halogen and C₁₋₆alkyl and-   R⁶ is as hereinbefore defined.

In another preferred embodiment (E8) the present invention relates tocompounds of general formulae (1a) and (1b), wherein

-   A together with R⁶ and the r substituents R⁷ has the partial    structure

-   R^(7d) and R^(7e) each independently denote methoxy;-   R^(7f) is selected from among fluorine and methyl and-   R⁶ is as hereinbefore defined.

In other preferred embodiments (E9) the present invention relates tocompounds of the preferred embodiments (E1) to (E8), wherein

-   R⁶ is selected from among hydrogen, R^(a2), R^(b2) and R^(a2)    substituted by one or more, identical or different R^(b2) and/or    R^(c2);-   each R^(a2) is independently selected from among C₁₋₆alkyl and 3-7    membered heterocycloalkyl;-   each R^(b2) is a suitable substituent and is independently selected    from among O═, —OR^(c2), —NR^(c2)R^(c2), —C(O)R^(c2),    —C(O)NR^(c2)R^(c2), —C(O)N(R^(g2))OR^(c2), —N(R^(g2))C(O)R^(c2),    —N(R^(g2))C(O)^(c2) and —N(R^(g2))C(O)NR^(c2)R^(c2),-   each R^(c2) independently denotes hydrogen or a group optionally    substituted by one or more, identical or different R^(d2) and/or    R^(e2), selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl and 3-7    membered heterocycloalkyl;-   each R^(d2) is a suitable substituent and is independently selected    from among —OR^(e2), —NR^(e2)R^(e2), —C(O)N(R^(g2))OR^(e2) and    —C(O)NR^(e2)R^(e2);-   each R^(e2) independently denotes hydrogen or a group optionally    substituted by one or more, identical or different R^(f2) and/or    R^(g2), selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl, 5-6-membered    heteroaryl and 3-7 membered heterocycloalkyl;-   each R^(f2) independently denotes —OR^(g2) and-   each R^(g2) is independently selected from among hydrogen, C₁₋₆alkyl    and C₄₋₉cycloalkylalkyl.

In other preferred embodiments (E10) the present invention relates tocompounds of the preferred embodiments (E9), wherein

-   R⁶ denotes —C(O)NHR^(g2) or —C(O)N(Me)R^(c2) and-   R^(c2) is as hereinbefore defined.

In other preferred embodiments (E11) the present invention relates tocompounds of the preferred embodiments (E9), wherein

-   R⁶ denotes —NHC(O)R^(c2) or —N(Me)C(O)R^(c2) and-   R^(c2) is as hereinbefore defined.

In other preferred embodiments (E12) the present invention relates tocompounds of the preferred embodiments (E9) to (E11), wherein

-   a heterocycloalkyl R^(a2) and/or R^(c2) is a heterocycloalkyl    selected from among piperidinyl, piperazinyl, pyrrolidinyl,    tetrahydropyranyl and morpholinyl.

In other preferred embodiments (E13) the present invention relates tocompounds of the preferred embodiments (E9), wherein

-   R⁶ denotes

-   R^(c2) is as hereinbefore defined.

In other preferred embodiments (E14) the present invention relates tocompounds of the preferred embodiments (E9), wherein

-   R⁶ denotes

-   R* denotes C₁₋₆alkyl.

In other preferred embodiments (E15) the present invention relates tocompounds of the preferred embodiments (E9), wherein

-   R⁶ is selected from among

In other preferred embodiments (E16) the present invention relates tocompounds of the preferred embodiments (E9), wherein

-   R⁶ is selected from among

In other preferred embodiments (E17) the present invention relates tocompounds of the preferred embodiments (E9), wherein

-   R⁶ is selected from among

In other preferred embodiments (E18) the present invention relates tocompounds of the preferred embodiments (E9), wherein

-   R⁶ is selected from among

In other preferred embodiments (E19) the present invention relates tocompounds of the preferred embodiments (E9), wherein

-   R⁶ is selected from among

In other preferred embodiments the present invention relates tocompounds of all the above-mentioned embodiments, wherein

-   each R^(a) is independently selected from among C₁₋₆alkyl,    C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl,    2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14    membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18    membered heteroarylalkyl;-   each R^(b) is a suitable group and is independently selected from    among ═O, —OR^(c), C₁₋₃haloalkyloxy, —OCF₃, —NR^(c)R^(c),    —ONR^(c)R^(c), —N(OR^(c))R^(c), —N(R^(g))NR^(c)R^(c), halogen, —CF₃,    —CN, —NO₂, —S(O)₂R^(c), —S(O)₂NR^(c)R^(c), —C(O)R^(c), —C(O)OR^(c),    —C(O)NR^(c)R^(c), —C(O)N(R^(g))NR^(c)R^(c), —C(O)N(R^(g))OR^(c),    —OC(O)R^(c), —OC(O)NR^(c)R^(c), —N(R^(g))C(O)R^(c),    —N(OR^(g))C(O)R^(c), —N(R^(g))S(O)₂R^(c), —N(R^(g))C(O)OR^(c) and    —N(R^(g))C(O)NR^(c)R^(c);-   each R^(c) independently denotes hydrogen or a group optionally    substituted by one or more, identical or different R^(d) and/or    R^(e), selected from among C₁₋₈alkyl, C₃₋₁₀cycloalkyl,    C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6 membered    heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered    heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 membered    heteroarylalkyl;-   each R^(d) is a suitable group and is independently selected from    among ═O, —OR^(e), C₁₋₃haloalkyloxy, —OCF₃, —NR^(e)R^(e),    —ONR^(e)R^(e), —N(R^(g))NR^(e)R^(e), halogen, —CF₃, —CN, —NO₂,    —S(O)₂R^(e), —S(O)₂NR^(e)R^(e), —C(O)R^(e), —C(O)OR^(e),    —C(O)NR^(e)R^(e), —C(O)N(R^(g))NR^(e)R^(e), —C(O)N(R^(g))OR^(e),    —OC(O)R^(e), —OC(O)NR^(e)R^(e), —N(R^(g))C(O)R^(e),    —N(OR^(g))C(O)R^(e), —N(R^(g))S(O)₂R^(e), —N(R^(g))C(O)OR^(e) and    —N(R^(g))C(O)NR^(e)R^(e);-   each R^(e) independently denotes hydrogen or a group optionally    substituted by one or more, identical or different R^(f) and/or    R^(g), selected from among C₁₋₆alkyl, C₃₋₈cycloalkyl,    C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6 membered    heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered    heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 membered    heteroarylalkyl;-   each R^(f) is a suitable group and is independently selected from    among halogen, —OR^(g) and —CF₃ and-   each R^(g) independently denotes hydrogen, C₁₋₆alkyl,    C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6    membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 membered    heterocycloalkyl, 5-12 membered heteroaryl or 6-18 membered    heteroarylalkyl.

All the above-mentioned preferred embodiments in terms of differentmolecular parts of the compounds according to the invention (1a) and(1b) may be combined with one another in any desired manner, thusproducing preferred compounds (1a) and (1b) according to the inventionor generic partial amounts of preferred compounds according to theinvention (1a) and (1b). Each individual embodiment or partial amountdefined by this combination is expressly also included and is an objectof the invention.

Particularly preferred compounds are:

-   23    4-[4-((1R,2R)-1-methanesulphonylamino-indan-2-yloxy)-5-trifluoromethyl-pyrimidin-2-ylamino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide-   24    2-fluoro-4-[4-((1R,2R)-1-methanesulphonylamino-indan-2-yloxy)-5-trifluoromethyl-pyrimidin-2-ylamino]-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide-   25    2-fluoro-4-{4-[(1R,2R)-1-(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide-   27    4-{4-[(1R,2R)-1-(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide-   28    2-fluoro-4-[4-((1R,2R)-2-methanesulphonylamino-cyclopentyloxy)-5-trifluoromethyl-pyrimidin-2-ylamino]-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide-   29    4-{4-[(1R,2R)-1-(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-3-methoxy-N-((3S,4S)-3-methoxy-1-methyl-piperidin-4-yl)-benzamide-   31    2-fluoro-4-{4-[(1R,2R)-1-(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-((3S,4S)-3-methoxy-1-methyl-piperidin-4-yl)-benzamide-   74    2-chloro-4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclohexyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide-   75    2-fluoro-4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclohexyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide-   77    4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclohexyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-3-methoxy-N-(4-methyl-piperazin-1-yl)-benzamide-   79    3-{4-[(1R,2R)-1-(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-4-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide-   84    2-chloro-4-{5-chloro-4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-pyrimidin-2-ylamino}-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide-   85    4-{5-chloro-4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-pyrimidin-2-ylamino}-2-fluoro-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide-   88    4-{5-chloro-4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-pyrimidin-2-ylamino}-2-fluoro-5-methoxy-N-(4-methyl-piperazin-1-yl)-benzamide-   90    N-((1R,2R)-2-{2-[4-(4-tert-butyl-piperazin-1-yl)-2-methoxy-phenylamino]-5-trifluoromethyl-pyrimidin-4-yloxy}-indan-1-yl)-N-methyl-methanesulphonamide-   100    2-chloro-4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(4-methyl-piperazin-1-yl)-benzamide-   101    2-fluoro-4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(4-methyl-piperazin-1-yl)-benzamide-   102    2-chloro-4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide-   103    2-fluoro-4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide-   104    2-fluoro-4-[4-((1R,2R)-2-methanesulphonylamino-cyclohexyloxy)-5-trifluoromethyl-pyrimidin-2-ylamino]-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide

The present invention further relates to hydrates, solvates, polymorphs,metabolites, derivatives and prodrugs of compounds of general formula(1a) and (1b).

In another aspect the invention relates to compounds of general formula(1a) and (1b)—or the pharmaceutically acceptable salts thereof—asmedicaments.

In another aspect the invention relates to compounds of general formula(1a) and (1b)—or the pharmaceutically acceptable salts thereof—for usein the treatment and/or prevention of cancer, infections, inflammationsand autoimmune diseases.

In another aspect the invention relates to compounds of general formula(1a) and (1b)—or the pharmaceutically acceptable salts thereof—for usein the treatment and/or prevention of cancer.

In another aspect the invention relates to compounds of general formula(1a) and (1b)—or the pharmaceutically acceptable salts thereof—for usein the treatment and/or prevention of prostate cancer, ovarian cancer,pancreatic cancer and bronchial cancer.

In another aspect the invention relates to a process for the treatmentand/or prevention of cancer comprising administering a therapeuticallyeffective amount of a compound of general formula (1a) or (1b)—or one ofthe pharmaceutically acceptable salts thereof—to a person.

In another aspect the invention relates to a pharmaceutical preparationcontaining as active substance one or more compounds of general formula(1a) and/or (1b)—or the pharmaceutically acceptable saltsthereof—optionally in combination with conventional excipients and/orcarriers.

In another aspect the invention relates to a pharmaceutical preparationcomprising a compound of general formula (1a) and/or (1b)—or one of thepharmaceutically acceptable salts thereof—and at least one othercytostatic or cytotoxic active substance different from formula (1a) and(1b).

Definitions

As used herein, the following definitions apply, unless statedotherwise:

Alkyl is made up of the sub-groups saturated hydrocarbon chains andunsaturated hydrocarbon chains, while the latter may be furthersubdivided into hydrocarbon chains with a double bond (alkenyl) andhydrocarbon chains with a triple bond (alkynyl). Alkenyl contains atleast one double bond, alkynyl contains at least one triple bond. If ahydrocarbon chain were to carry both at least one double bond and alsoat least one triple bond, by definition it would belong to the alkynylsub-group. All the sub-groups mentioned above may further be dividedinto straight-chain (unbranched) and branched. If an alkyl issubstituted, the substitution may be mono- or polysubstitution in eachcase, at all the hydrogen-carrying carbon atoms, independently of oneanother. Examples of representatives of individual sub-groups are listedbelow.

Straight-Chain (Unbranched) or Branched Saturated Hydrocarbon Chains:

-   methyl; ethyl; n-propyl; isopropyl (1-methylethyl); n-butyl;    1-methylpropyl; isobutyl (2-methylpropyl); sec.-butyl    (1-methylpropyl); tert.-butyl (1,1-dimethylethyl); n-pentyl;    1-methylbutyl; 1-ethylpropyl; isopentyl (3-methylbutyl); neopentyl    (2,2-dimethyl-propyl); n-hexyl; 2,3-dimethylbutyl;    2,2-dimethylbutyl; 3,3-dimethylbutyl; 2-methyl-pentyl;    3-methylpentyl; n-heptyl; 2-methylhexyl; 3-methylhexyl;    2,2-dimethylpentyl; 2,3-dimethylpentyl; 2,4-dimethylpentyl;    3,3-dimethylpentyl; 2,2,3-trimethylbutyl; 3-ethylpentyl; n-octyl;    n-nonyl; n-decyl etc.    Straight-Chain (Unbranched) or Branched Alkenyl:-   vinyl(ethenyl); prop-1-enyl; allyl(prop-2-enyl); isopropenyl;    but-1-enyl; but-2-enyl; but-3-enyl; 2-methyl-prop-2-enyl;    2-methyl-prop-1-enyl; 1-methyl-prop-2-enyl; 1-methyl-prop-1-enyl;    1-methylidenepropyl; pent-1-enyl; pent-2-enyl; pent-3-enyl;    pent-4-enyl; 3-methyl-but-3-enyl; 3-methyl-but-2-enyl;    3-methyl-but-1-enyl; hex-1-enyl; hex-2-enyl; hex-3-enyl; hex-4-enyl;    hex-5-enyl; 2,3-dimethyl-but-3-enyl; 2,3-dimethyl-but-2-enyl;    2-methylidene-3-methylbutyl; 2,3-dimethyl-but-1-enyl;    hexa-1,3-dienyl; hexa-1,4-dienyl; penta-1,4-dienyl;    penta-1,3-dienyl; buta-1,3-dienyl; 2,3-dimethylbuta-1,3-diene etc.    Straight-Chain (Unbranched) or Branched Alkynyl:-   ethynyl; prop-1-ynyl; prop-2-ynyl; but-1-ynyl; but-2-ynyl;    but-3-ynyl; 1-methyl-prop-2-ynyl etc.

By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyletc. without any further definition are meant saturated hydrocarbongroups with the corresponding number of carbon atoms, all the isomericforms being included.

By the terms propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl,nonenyl, decenyl etc. without any further definition are meantunsaturated hydrocarbon groups with the corresponding number of carbonatoms and a double bond, all the isomeric forms, i.e. (Z)/(E) isomers,being included where applicable.

By the terms butadienyl, pentadienyl, hexadienyl, heptadienyl,octadienyl, nonadienyl, decadienyl etc. without any further definitionare meant unsaturated hydrocarbon groups with the corresponding numberof carbon atoms and two double bonds, all the isomeric forms, i.e.(Z)/(E) isomers, being included where applicable.

By the terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl,nonynyl, decynyl etc. without any further definition are meantunsaturated hydrocarbon groups with the corresponding number of carbonatoms and a triple bond, all the isomeric forms being included.

By the term heteroalkyl are meant groups which can be derived from thealkyl as defined above in its broadest sense if, in the hydrocarbonchains, one or more of the groups —CH₃ are replaced independently of oneanother by the groups —OH, —SH or —NH₂, one or more of the groups —CH₂—are replaced independently of one another by the groups —O—, —S— or—NH—, one or more of the groups

are replaced by the group

one or more of the groups ═CH— are replaced by the group ═N—, one ormore of the groups ═CH₂ are replaced by the group ═NH or one or more ofthe groups ≡CH are replaced by the group ≡N, while overall there mayonly be a maximum of three heteroatoms in a heteroalkyl, there must beat least one carbon atom between two oxygen atoms and between twosulphur atoms or between one oxygen and one sulphur atom and the groupas a whole must be chemically stable.

It is immediately apparent from the indirect definition/derivation fromalkyl that heteroalkyl is made up of the sub-groups saturatedhydrocarbon chains with heteroatom(s), heteroalkenyl and heteroalkynyl,and one further subdivision may be carried out into straight-chain(unbranched) and branched. If a heteroalkyl is substituted, thesubstitution may be mono- or polysubstitution in each case, at all thehydrogen-carrying oxygen, sulphur, nitrogen and/or carbon atoms,independently of one another. Heteroalkyl itself may be linked to themolecule as a substituent both via a carbon atom and via a heteroatom.

Typical Examples are Listed Below:

-   dimethylaminomethyl; dimethylaminoethyl (1-dimethylaminoethyl;    2-dimethyl-aminoethyl); dimethylaminopropyl (1-dimethylaminopropyl,    2-dimethylaminopropyl, 3-dimethylaminopropyl); diethylaminomethyl;    diethylaminoethyl (1-diethylaminoethyl, 2-diethylaminoethyl);    diethylaminopropyl (1-diethylaminopropyl, 2-diethylamino-propyl,    3-diethylaminopropyl); diisopropylaminoethyl    (1-diisopropylaminoethyl, 2-di-isopropylaminoethyl);    bis-2-methoxyethylamino;    [2-(dimethylamino-ethyl)-ethyl-amino]-methyl;    3-[2-(dimethylamino-ethyl)-ethyl-amino]-propyl; hydroxymethyl;    2-hydroxy-ethyl; 3-hydroxypropyl; methoxy; ethoxy; propoxy;    methoxymethyl; 2-methoxyethyl etc.

Halogen denotes fluorine, chlorine, bromine and/or iodine atoms.

Haloalkyl is derived from alkyl as hereinbefore defined in its broadestsense, when one or more hydrogen atoms of the hydrocarbon chain arereplaced independently of one another by halogen atoms, which may beidentical or different. It is immediately apparent from the indirectdefinition/derivation from alkyl that haloalkyl is made up of thesub-groups saturated halohydrocarbon chains, haloalkenyl andhaloalkynyl, and further subdivision may be made into straight-chain(unbranched) and branched. If a haloalkyl is substituted, thesubstitution may be mono- or polysubstitution in each case, at all thehydrogen-carrying carbon atoms, independently of one another.

Typical examples include —CF₃; —CHF₂; —CH₂F; —CF₂CF₃; —CHFCF₃; —CH₂CF₃;—CF₂CH₃; —CHFCH₃; —CF₂CF₂CF₃; —CF₂CH₂CH₃; —CF═CF₂; —CCl═CH₂; —CBr═CH₂;—Cl═CH₂; —C≡C—CF₃; —CHFCH₂CH₃; and —CHFCH₂CF₃.

Cycloalkyl is made up of the sub-groups monocyclic hydrocarbon rings,bicyclic hydrocarbon rings and spirohydrocarbon rings, while eachsub-group may be further subdivided into saturated and unsaturated(cycloalkenyl). The term unsaturated means that in the ring system inquestion there is at least one double bond, but no aromatic system isformed. In bicyclic hydrocarbon rings two rings are linked such thatthey have at least two carbon atoms in common. In spirohydrocarbon ringsone carbon atom (spiroatom) is shared by two rings. If a cycloalkyl issubstituted, the substitution may be mono- or polysubstitution in eachcase, at all the hydrogen-carrying carbon atoms, independently of oneanother. Cycloalkyl itself may be linked to the molecule as substituentvia any suitable position of the ring system.

Typical examples of individual sub-groups are listed below.

Monocyclic Saturated Hydrocarbon Rings:

-   cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cycloheptyl etc.    Monocyclic Unsaturated Hydrocarbon Rings:-   cycloprop-1-enyl; cycloprop-2-enyl; cyclobut-1-enyl;    cyclobut-2-enyl; cyclopent-1-enyl; cyclopent-2-enyl;    cyclopent-3-enyl; cyclohex-1-enyl; cyclohex-2-enyl; cyclohex-3-enyl;    cyclohept-1-enyl; cyclohept-2-enyl; cyclohept-3-enyl;    cyclohept-4-enyl; cyclobuta-1,3-dienyl; cyclopenta-1,4-dienyl;    cyclopenta-1,3-dienyl; cyclopenta-2,4-dienyl; cyclohexa-1,3-dienyl;    cyclohexa-1,5-dienyl; cyclohexa-2,4-dienyl; cyclohexa-1,4-dienyl;    cyclohexa-2,5-dienyl etc.    Saturated and Unsaturated Bicyclic Hydrocarbon Rings:-   bicyclo[2.2.0]hexyl; bicyclo[3.2.0]heptyl; bicyclo[3.2.1]octyl;    bicyclo[2.2.2]octyl; bicyclo[4.3.0]nonyl(octahydroindenyl);    bicyclo[4.4.0]decyl(decahydronaphthalene);    bicyclo[2,2,1]heptyl(norbornyl);    (bicyclo[2.2.1]hepta-2,5-dienyl(norborna-2,5-dienyl);    bicyclo[2,2,1]hept-2-enyl(norbornenyl);    bicyclo[4.1.0]heptyl(norcaranyl); bicyclo-[3.1.1]heptyl(pinanyl)    etc.    Saturated and Unsaturated Spirohydrocarbon Rings:-   spiro[2.5]octyl, spiro[3.3]heptyl, spiro[4.5]dec-2-ene etc.

Cycloalkylalkyl denotes the combination of the above-defined groupsalkyl and cycloalkyl, in each case in their broadest sense. The alkylgroup as substituent is directly linked to the molecule and is in turnsubstituted by a cycloalkyl group. The alkyl and cycloalkyl may belinked in both groups via any carbon atoms suitable for this purpose.The respective sub-groups of alkyl and cycloalkyl are also included inthe combination of the two groups.

Aryl denotes mono-, bi- or tricyclic carbon rings with at least onearomatic ring. If an aryl is substituted, the substitution may be mono-or polysubstitution in each case, at all the hydrogen-carrying carbonatoms, independently of one another. Aryl itself may be linked to themolecule as substituent via any suitable position of the ring system.Typical examples include phenyl, naphthyl, indanyl (2,3-dihydroindenyl),1,2,3,4-tetrahydronaphthyl and fluorenyl.

Carbobicyclic ring systems comprise bicyclic carbon rings with at leastone aromatic ring, such as for example bicyclooctatrienyl, indanyl,1,2,3,4-tetrahydronaphthyl and 6,7,8,9-tetrahydrobenzocycloheptyl.

Arylalkyl denotes the combination of the groups alkyl and aryl ashereinbefore defined, in each case in their broadest sense. The alkylgroup as substituent is directly linked to the molecule and is in turnsubstituted by an aryl group. The alkyl and aryl may be linked in bothgroups via any carbon atoms suitable for this purpose. The respectivesub-groups of alkyl and aryl are also included in the combination of thetwo groups.

Typical examples include benzyl; 1-phenylethyl; 2-phenylethyl;phenylvinyl; phenylallyl etc.

Heteroaryl denotes monocyclic aromatic rings, bi- or polycyclic ringsystems with at least one aromatic ring, which, compared withcorresponding aryl or cycloalkyl, contain instead of one or more carbonatoms one or more identical or different heteroatoms, selectedindependently of one another from among nitrogen, sulphur and oxygen,while the resulting group must be chemically stable. If a heteroaryl issubstituted, the substitution may be mono- or polysubstitution in eachcase, at all the hydrogen-carrying carbon and/or nitrogen atoms,independently of one another. Heteroaryl itself as substituent may belinked to the molecule via any suitable position of the ring system,both carbon and nitrogen.

Typical examples are listed below.

Monocyclic Heteroaryls:

-   furyl; thienyl; pyrrolyl; oxazolyl; thiazolyl; isoxazolyl;    isothiazolyl; pyrazolyl; imidazolyl; triazolyl; tetrazolyl;    oxadiazolyl; thiadiazolyl; pyridyl; pyrimidyl; pyridazinyl;    pyrazinyl; triazinyl; pyridyl-N-oxide; pyrrolyl-N-oxide;    pyrimidinyl-N-oxide; pyridazinyl-N-oxide; pyrazinyl-N-oxide;    imidazolyl-N-oxide; isoxazolyl-N-oxide; oxazolyl-N-oxide;    thiazolyl-N-oxide; oxadiazolyl-N-oxide; thiadiazolyl-N-oxide;    triazolyl-N-oxide; tetrazolyl-N-oxide etc.    Bicyclic and Polycyclic Heteroaryls:-   indolyl; isoindolyl; benzofuryl; benzothienyl; benzoxazolyl;    benzothiazolyl; benzisoxazolyl; benzisothiazolyl; benzimidazolyl;    indazolyl; isoquinolinyl; quinolinyl; quinoxalinyl; cinnolinyl;    phthalazinyl; quinazolinyl; benzotriazinyl; indolizinyl;    oxazolopyridyl; imidazopyridyl; naphthyridinyl; indolinyl;    isochromanyl; chromanyl; tetrahydroisoquinolinyl; isoindolinyl;    isobenzotetrahydrofuryl; isobenzotetrahydrothienyl; isobenzothienyl;    benzoxazolyl; pyridopyridyl; benzotetrahydrofuryl;    benzotetrahydro-thienyl; purinyl; benzodioxolyl; phenoxazinyl;    phenothiazinyl; pteridinyl; benzothiazolyl; imidazopyridyl;    imidazothiazolyl; dihydrobenzisoxazinyl; benzisoxazinyl;    benzoxazinyl; dihydrobenzisothiazinyl; benzopyranyl;    benzothiopyranyl; coumarinyl; isocumarinyl; chromonyl; chromanonyl;    tetrahydroquinolinyl; dihydroquinolinyl; dihydroquinolinonyl;    dihydroisoquinolinonyl; dihydrocumarinyl; dihydroisocumarinyl;    isoindolinonyl; benzodioxanyl; benzoxazolinonyl; quinolinyl-N-oxide;    indolyl-N-oxide; indolinyl-N-oxide; isoquinolyl-N-oxide;    quinazolinyl-N-oxide; quinoxalinyl-N-oxide; phthalazinyl-N-oxide;    indolizinyl-N-oxide; indazolyl-N-oxide; benzothiazolyl-N-oxide;    benzimidazolyl-N-oxide; benzo-thiopyranyl-S-oxide and    benzothiopyranyl-S,S-dioxide etc.

Heterobicyclic ring systems comprise for example dihydrobenzofuryl,dihydroisobenzofuryl, dihydroindolyl dihydroisoindolyl,dihydrobenzothiophenyl, dihydroisobenzothiophenyl, dihydroindazolyl,1,2-benzisoxazolyl, 1H-1,2-benzisoxazolyl, 1,2-benzothiazolyl,2,3-tetrahydro-1H-isoquinolinyl, 3,4-tetrahydro-2H-isoquinolinyl,tetrahydroquinolinyl, chromanyl, isochromanyl, isochromenyl,thiochromanyl, thiochromenyl, dihydro-2H-phthalazinyl,tetrahydrocinnolinyl, tetrahydroquinazolinyl, tetrahydrobenzodiazepinyland tetrahydrobenzoxazepinyl.

Heteroarylalkyl denotes the combination of the alkyl and heteroarylgroups defined hereinbefore, in each case in their broadest sense. Thealkyl group as substituent is directly linked to the molecule and is inturn substituted by a heteroaryl group. The linking of the alkyl andheteroaryl may be achieved on the alkyl side via any carbon atomssuitable for this purpose and on the heteroaryl side by any carbon ornitrogen atoms suitable for this purpose. The respective sub-groups ofalkyl and heteroaryl are also included in the combination of the twogroups.

By the term heterocycloalkyl are meant groups which are derived from thecycloalkyl as hereinbefore defined if in the hydrocarbon rings one ormore of the groups —CH₂— are replaced independently of one another bythe groups —O—, —S— or —NH— or one or more of the groups ═CH— arereplaced by the group ═N—, while not more than five heteroatoms may bepresent in total, there must be at least one carbon atom between twooxygen atoms and between two sulphur atoms or between one oxygen and onesulphur atom and the group as a whole must be chemically stable.Heteroatoms may simultaneously be present in all the possible oxidationstages (sulphur→sulphoxide —SO—, sulphone —SO₂—; nitrogen→N-oxide). Itis immediately apparent from the indirect definition/derivation fromcycloalkyl that heterocycloalkyl is made up of the sub-groups monocyclichetero-rings, bicyclic hetero-rings and spirohetero-rings, while eachsub-group can also be further subdivided into saturated and unsaturated(heterocycloalkenyl). The term unsaturated means that in the ring systemin question there is at least one double bond, but no aromatic system isformed. In bicyclic hetero-rings two rings are linked such that theyhave at least two atoms in common. In spirohetero-rings one carbon atom(spiroatom) is shared by two rings. If a heterocycloalkyl issubstituted, the substitution may be mono- or polysubstitution in eachcase, at all the hydrogen-carrying carbon and/or nitrogen atoms,independently of one another. Heterocycloalkyl itself as substituent maybe linked to the molecule via any suitable position of the ring system.

Typical examples of individual sub-groups are listed below.

Monocyclic Heterorinqs (Saturated and Unsaturated):

-   tetrahydrofuryl; pyrrolidinyl; pyrrolinyl; imidazolidinyl;    thiazolidinyl; imidazolinyl; pyrazolidinyl; pyrazolinyl;    piperidinyl; piperazinyl; oxiranyl; aziridinyl; azetidinyl;    1,4-dioxanyl; azepanyl; diazepanyl; morpholinyl; thiomorpholinyl;    homomorpholinyl; homopiperidinyl; homopiperazinyl;    homothiomorpholinyl; thiomorpholinyl-5-oxide;    thiomorpholinyl-S,S-dioxide; 1,3-dioxolanyl; tetrahydropyranyl;    tetrahydrothiopyranyl; [1,4]-oxazepanyl; tetrahydrothienyl;    homothiomorpholinyl-S,S-dioxide; oxazolidinonyl; dihydropyrazolyl;    dihydropyrrolyl; dihydropyrazinyl; dihydropyridyl;    dihydro-pyrimidinyl; dihydrofuryl; dihydropyranyl;    tetrahydrothienyl-S-oxide; tetrahydrothienyl-S,S-dioxide;    homothiomorpholinyl-S-oxide; 2,3-dihydroazet; 2H-pyrrolyl;    4H-pyranyl; 1,4-dihydropyridinyl etc.    Bicyclic Heterorinqs (Saturated and Unsaturated):-   8-azabicyclo[3.2.1]octyl; 8-azabicyclo[5.1.0]octyl;    2-oxa-5-azabicyclo[2.2.1]heptyl; 8-oxa-3-aza-bicyclo[3.2.1]octyl;    3,8-diaza-bicyclo[3.2.1]octyl; 2,5-diaza-bicyclo-[2.2.1]heptyl;    1-aza-bicyclo[2.2.2]octyl; 3,8-diaza-bicyclo[3.2.1]octyl;    3,9-diaza-bicyclo[4.2.1]nonyl; 2,6-diaza-bicyclo[3.2.2]nonyl;    hexahydro-furo[3,2-b]furyl; etc.    Spiro-Heterorinqs (Saturated and Unsaturated):-   1,4-dioxa-spiro[4.5]decyl; 1-oxa-3,8-diaza-spiro[4.5]decyl;    2,6-diaza-spiro[3.3]heptyl; 2,7-diaza-spiro[4.4]nonyl;    2,6-diaza-spiro[3.4]octyl; 3,9-diaza-spiro[5.5]undecyl;    2,8-diaza-spiro[4.5]decyl etc.

HeterocycloalkvIalkyl denotes the combination of the alkyl andheterocycloalkyl groups defined hereinbefore, in each case in theirbroadest sense. The alkyl group as substituent is directly linked to themolecule and is in turn substituted by a heterocycloalkyl group. Thelinking of the alkyl and heterocycloalkyl may be achieved on the alkylside via any carbon atoms suitable for this purpose and on theheterocycloalkyl side by any carbon or nitrogen atoms suitable for thispurpose. The respective sub-groups of alkyl and heterocycloalkyl arealso included in the combination of the two groups.

By the term “suitable substituent” is meant a substituent that on theone hand is fitting on account of its valency and on the other handleads to a system with chemical stability.

By “prodrug” is meant an active substance in the form of its precursormetabolite. A distinction may be made between partly multi-partcarrier-prodrug systems and biotransformation systems. The lattercontain the active substance in a form that requires chemical orbiological metabolisation. The skilled man will be familiar with prodrugsystems of this kind (Sloan, Kenneth B.; Wasdo, Scott C. The role ofprodrugs in penetration enhancement. Percutaneous Penetration Enhancers(2nd Edition) (2006). 51-64; Lloyd, Andrew W. Prodrugs. Smith andWilliams' Introduction to the Principles of Drug Design and Action (4thEdition) (2006), 211-232; Neervannan, Seshadri. Strategies to impactsolubility and dissolution rate during drug lead optimization: saltselection and prodrug design approaches. American Pharmaceutical Review(2004), 7(5), 108.110-113). A suitable prodrug contains for example asubstance of the general formulae which is linked via an enzymaticallycleavable linker (e.g. carbamate, phosphate, N-glycoside or a disulphidegroup to a dissolution-improving substance (e.g. tetraethyleneglycol,saccharides, amino acids). Carrier-prodrug systems contain the activesubstance as such, bound to a masking group which can be cleaved by thesimplest possible controllable mechanism. The function of masking groupsaccording to the invention in the compounds according to the inventionis to neutralize the charge for improving cell uptake. If the compoundsaccording to the invention are used with a masking group, these may alsoadditionally influence other pharmacological parameters, such as forexample oral bioavailability, tissue distribution, pharmacokinetics andstability against non-specific phosphatases. The delayed release of theactive substance may also involve a sustained-release effect. Inaddition, modified metabolisation may occur, thus resulting in a higherefficiency of the active substance or organic specificity. In the caseof a prodrug formulation, the masking group or a linker that binds themasking group to the active substance is selected such that the prodrugis sufficiently hydrophilic to be dissolved in the blood serum, hassufficient chemical and enzymatic stability to reach the activity siteand is also sufficiently hydrophilic to ensure that it is suitable fordiffusion-controlled membrane transport. Furthermore, it should allowchemically or enzymatically induced release of the active substancewithin a reasonable period and, it goes without saying, the auxiliarycomponents released should be non-toxic. Within the scope of theinvention, however, the compound without a mask or linker, and a mask,may be regarded as a prodrug which first of all has to be prepared inthe cell from the ingested compound by enzymatic and biochemicalprocesses.

List of abbreviations Bu butyl c concentration cHex cyclohexane d day(s)TLC thin layer chromatography DCM dichloromethane DIPEAN-ethyl-N,N-diisopropylamine (Hünig base) DMF N,N-dimethylformamide DMSOdimethylsulphoxide EA ethyl acetate ESI electron spray ionization Etethyl EtOH ethanol h hour(s) hex hexyl HPLC high performance liquidchromatography i iso IR infrared spectroscopy Me methyl MeOH methanolmin minute(s) MPLC medium pressure liquid chromatography MS massspectrometry NMP N-methylpyrrolidone NP normal phase Pd₂dba₃ tris(dibenzylideneacetone)dipalladium(0) Ph phenyl rac racemic R_(f) (Rf)retention factor RP reversed phase RT ambient temperature temp.temperature tert. tertiary THF tetrahydrofuran t_(Ret.) retention time(HPLC) UV ultraviolet

Features and advantages of the present invention will become apparentfrom the following detailed Examples which illustrate the fundamentalsof the invention by way of example, without restricting its scope:

Preparation of the Compounds According to the Invention

General

All the reactions are carried out—unless stated otherwise—incommercially obtainable apparatus using methods conventionally used inchemical laboratories.

Air- and/or moisture-sensitive starting materials are stored underprotective gas and corresponding reactions and manipulations using themare carried out under protective gas (nitrogen or argon).

Microwave reactions are carried out in an Initiator made by Biotage oran Explorer made by CEM in sealed containers (preferably 2, 5 or 20 mL),preferably with stirring.

Chromatography

For the preparative medium pressure chromatography (MPLC, normal phase)silica gel is used which is made by Millipore (named: Granula SilicaSi-60A 35-70 μm) or C-18 RP-silica gel (RP-phase) made by Macherey Nagel(named: Polygoprep 100-50 C18).

The thin layer chromatography is carried out on ready-made silica gel 60TLC plates on glass (with fluorescence indicator F-254) made by Merck.

The preparative high pressure chromatography (HPLC) is carried out usingcolumns made by Waters (named: XTerra Prep. MS C18, 5 μM, 30×100 mm orXTerra Prep. MS C18, 5 μm, 50×100 mm OBD or Symmetrie C18, 5 μm, 19×100mm or Sunfire C18 OBD, 19×100 mm, 5 μm or Sunfire Prep C 10 μm OBD50×150 mm or X-Bridge Prep C18 5 μm OBD 19×50 mm), Agilent (named:Zorbax SB—C8 5 μm PrepHT 21.2×50 mm) and Phenomenex (named: Gemini C18 5μm AXIA 21.2×50 mm or Gemini C18 10 μm 50×150 mm), the analytical HPLC(reaction control) is carried out with columns made by Agilent (named:Zorbax SB—C8, 5 μm, 21.2×50 mm or Zorbax SB—C8 3.5 μm 2.1×50 mm) andPhenomenex (named: Gemini C18 3 μm 2×30 mm).

HPLC Mass Spectroscopy/UV Spectrometry

The retention times/MS-ESI⁺for characterising the examples are obtainedusing an HPLC-MS apparatus (high performance liquid chromatography withmass detector) made by Agilent. Compounds that elute with the injectionpeak are given the retention time t_(Ret.)=0.00.

-   Method A:

Column: Waters, Xterra MS C18, 2.5 μm, 2.1 × 30 mm, Part. No. 186000592Eluant: A: H₂O with 0.1% HCOOH; B: acetonitrile (HPLC grade) Detection:MS: Positive and negative mode Mass range: 120-900 m/z Fragmentor: 120Gain EMV: 1; Threshold: 150; Stepsize: 0.25; UV: 254 nm; Bandwidth: 1Injection: Inj. Vol. 5 μL Separation: Flow 1.10 mL/min Column temp.: 40°C. Gradient:     0.00 min:  5% solvent B 0.00-2.50 min:  5% → 95%solvent B 2.50-2.80 min: 95% solvent B 2.81-3.10 min: 95% → 5% solvent B

-   Method B:

Column: Waters, Xterra MS C18, 2.5 μm, 2.1 × 50 mm, Part. No. 186000594Eluant: A: H₂O with 0.1% HCOOH; B: acetonitrile with 0.1% HCOOHDetection: MS: Positive and negative mode Mass range: 100-1200 m/zFragmentor: 70 Gain EMV: Threshold: 1 mAU; Stepsize: 2 nm; UV: 254 nm aswell as 230 nm Injection: Standard 1 μL Flow: 0.6 mL/min Column temp.:35° C. Gradient:     0.00 min:  5% solvent B 0.00-2.50 min:  5% → 95%solvent B 2.50-4.00 min: 95% solvent B 4.00-4.50 min: 95% → 5% solvent B4.50-6.00 min: 95% solvent A

-   Method C

Column: Waters, X-Bridge C18, 3.5 μm, 2.1 × 50 mm, Eluant: A: H₂O with10 mM NH₃; B: acetonitrile with 10 nM NH₃ Detection: MS: Positive andnegative mode Mass range: 100-800 m/z Fragmentor: 70 Gain EMV:Threshold: 1 mAU; Stepsize: 2 nm; UV: 220-320 nm Injection: Standard 1μL Flow: 0.8 mL/min Column temp.: 25° C. Gradient:     0.00 min:  2%solvent B 0.00-4.00 min:  2% → 98% solvent B 4.00-6.00 min: 98% solventB

-   Method D

Column: Waters, X-Bridge C18, 3.5 μm, 2.1 × 50 mm, Eluant: A: H₂O with0.1% HCOOH; B: acetonitrile with 0.1% HCOOH Detection: MS: Positive andnegative mode Mass range: 100-800 m/z Fragmentor: 70 Gain EMV:Threshold: 1 mAU; Stepsize: 2 nm; UV: 220-320 nm Injection: Standard 1μL Flow: 0.8 mL/min Column temp.: 35° C. Gradient:     0.00 min:  2%solvent B 0.00-4.00 min:  2% → 98% solvent B 4.00-6.00 min: 98% solventB

-   Method E

Column: Phenomenex Gemini C18, 3.0 μm, 2.0 × 50 mm, Eluant: A: H₂O with10 mM NH₃; B: acetonitrile with 10 nM NH₃ Detection: MS: Positive andnegative mode Mass range: 100-800 m/z Fragmentor: 70 Gain EMV:Threshold: 1 mAU; Stepsize: 2 nm; UV: 220-320 nm Injection: Standard 1μL Flow: 1.0 mL/min Column temp.: 35° C. Gradient:     0.00 min:  2%solvent B 0.00-3.50 min:  2% → 98% solvent B 3.50-6.00 min: 98% solventB

-   Method F

Column: Phenomenex Gemini C18, 3.0 μm, 2.0 × 50 mm, Eluant: A: H₂O with0.1% HCOOH; B: acetonitrile with 0.1% HCOOH Detection: MS: Positive andnegative mode Mass range: 100-800 m/z Fragmentor: 70 Gain EMV:Threshold: 1 mAU; Stepsize: 2 nm; UV: 220-320 nm Injection: Standard 1μL Flow: 1.0 mL/min Column temp.: 35° C. Gradient:     0.00 min:  2%solvent B 0.00-3.50 min:  2% → 98% solvent B 3.50-6.00 min: 95% solventB

The compounds according to the invention are prepared by the methods ofsynthesis described below, in which the substituents of the generalformulae have the meanings specified hereinbefore. These methods areintended to illustrate the invention without restricting it to theircontent or limiting the scope of the compounds claimed to theseExamples. Where the preparation of the starting compounds is notdescribed, they are commercially obtainable or may be preparedanalogously to known compounds or methods described herein. Substancesdescribed in the literature are prepared according to the publishedmethods of synthesis.

Example compounds of type I are prepared from 2,4-dichloropyrimidinesA-1 substituted by R¹, by nucleophilic aromatic substitution using analcohol R^(z)—OH and an amine R^(z)—NH₂. The order of substitutiondepends to a great extent on the nucleophiles used, the reactionconditions (acidic or basic reaction conditions and the addition ofLewis acids) and the substituent R¹. R^(y) and R^(z) are in each casesuitable groups for obtaining Example compounds according to theinvention.

The nucleophilic aromatic substitutions at A-1, A-2 and A-3 are carriedout according to methods known from the literature in common solvents,such as e.g. THF, DCM, NMP, EtOH, MeOH, DMSO or DMF using a base, suchas for example DIPEA, Cs₂CO₃ or NaH or an acid such as for example HCl.The amines R^(y)NH₂ used, and the alcohols R^(z)—OH are commerciallyobtainable or are synthesised according to methods known from theliterature. The 2-amino-4-oxo-pyrimidines of type I which may beobtained directly by these methods may then be further modified in R^(y)and R^(z) in a manner known from or analogous to the literature to formfurther 2-amino-4-oxo-pyrimidines of type I. Thus, for example, thegroups R^(y) and R^(z) of directly obtainable 2-amino-4-oxo-pyrimidinesof type I, which consist of a carboxylic acid-, sulphonic acid-,halogen- or amino-substituted aryl, heteroaryl, cycloalkyl orheterocycloalkyl, may be modified by reactions of substitution (at theheteroaryl itself), alkylation, acylation, amination or addition.

Preparation of the Starting Compounds

If their preparation is not described, the starting materials arecommercially obtainable, known from the literature or easily obtainableby the skilled man using general methods, for example

-   4-amino-2-chloro-5-methoxy-benzoic acid,    4-amino-2-fluoro-5-methoxy-benzoic acid (WO 2008/003958);-   4-(4-chloro-5-trifluoromethyl-pyrimidin-2-yl-amino)-3-methoxy-benzoic    acid,    4-(4-chloro-5-trifluoromethyl-pyrimidin-2-yl-amino)-2-chloro-5-methoxy-benzoic    acid and    4-(4-chloro-5-trifluoromethyl-pyrimidin-2-yl-amino)-2-fluoro-5-methoxy-benzoic    acid (analogously to WO 2007/003596);-   tert-butyl 4-benzylamino-3-fluoro-piperidine-1-carboxylate (J. Med.    Chem. 1999, 42(12), 2087-2104);-   benzyl    (3S,4S)-4-tert-butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylate    and benzyl    (3R,4R)-4-tert-butoxycarbonylamino-3-hydroxy-piperidine-1-carboxylate    (WO 2004/058144).

4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide

4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-benzoic acid (2.0 g)is suspended in 70 mL toluene, mixed with thionyl chloride (0.84 mL) andheated to 120° C. for 2 h with stirring. The reaction mixture is left tocool to RT and the solvent is eliminated using the rotary evaporator.The residue is suspended in 50 mL THF, cooled to 0° C. and a solution of4-amino-1-methylpiperidine (0.66 g) and DIPEA (1.97 mL), dissolved in 20mL THF, is added dropwise. The reaction mixture is slowly brought up toRT and stirred for a further 12 h at RT. The reaction mixture is cooledto 0° C., the product is filtered off and used without any furtherpurification.

N-((1R,2R)-2-hydroxy-indan-1-yl)-N-methyl-methanesulphonamide a)(1R,2R)-2-(tert-butyl-dimethyl-silanyloxy)-indan-1-ylamine

(1R,2R)-1-amino-2-indanol (2.00 g) is suspended in 20 mL DCM andcombined with triethylamine (3.61 mL) as well as DMAP (0.32 g). Thentert-butyldimethylchlorosilane (4.04 g in 2 mL CH₂Cl₂) is added. Thereaction mixture is stirred for 16 h at RT and, once the reaction iscomplete, it is mixed with water, extracted with CH₂Cl₂ and the organicphase is freed from the solvent using the rotary evaporator. The residueis taken up in MeOH and isolate is added. After elimination of thesolvent once again the mixture is purified by normal phasechromatography (CH₂Cl₂/EA). The product-containing fractions arecombined and freed from the solvent using the rotary evaporator.

b)N-[(1R,2R)-2-(tert-butyl-dimethyl-silanyloxy)-indan-1-yl]-methanesulphonamide

(1R,2R)-2-(tert-butyl-dimethyl-silanyloxy)-indan-1-ylamine (1.60 g) isdissolved in 16 mL DCM and combined with triethylamine (2.54 mL). Thenmethanesulphonyl chloride (0.61 mL in 5 mL DCM) is added dropwise. Thereaction mixture is stirred for 2 h and after elimination of the solventit is purified by normal phase chromatography (cHex/EA). Theproduct-containing fractions are combined and freed from the solventusing the rotary evaporator.

c)N-[(1R,2R)-2-(tert-butyl-dimethyl-silanyloxy)-indan-1-yl]-N-methyl-methanesulphonamide

N-[(1R,2R)-2-(tert-butyl-dimethyl-silanyloxy)-indan-1-yl]-methanesulphonamide(0.50 g) is dissolved in 2 mL DMF and mixed with Cs₂CO₃ (0.96 g, 2.93mmol) and MeI (0.10 mL). The reaction mixture is stirred for 2 h and,once the reaction has ended, combined with DCM and NaOH (1 N). Theorganic phase is dried on MgSO₄ and freed from the solvent using therotary evaporator. After dissolving in acetonitrile water is added. Theprecipitate formed is filtered off, washed with water and taken up inDCM. After drying on MgSO₄ the solvent is eliminated using the rotaryevaporator.

d) N-((1R,2R)-2-hydroxy-indan-1-yl)-N-methyl-methanesulphonamide

N-[(1R,2R)-2-(tert-butyl-dimethyl-silanyloxy)-indan-1-yl]-N-methyl-methanesulphonamide(0.53 g) is dissolved in 5 mL THF, combined with Bu₄NF (5 mL of a 1 Nsolution in THF) and stirred for 2 h at RT. After the reaction iscomplete the reaction mixture is freed from the solvent. After theaddition of CH₂Cl₂ it is extracted with HCl (aqu., 1 N). The organicphase is dried on MgSO₄. After elimination of the solvent the mixture ispurified by normal phase chromatography (CH₂Cl₂, MeOH). Theproduct-containing fractions are combined and freed from the solventusing the rotary evaporator.

N-((1R.2R)-2-hydroxy-indan-1-yl)-acetamide

(1R,2S)-1-amino-2-indanol (2.0 g) is suspended in 100 mL CH₂Cl₂ and atRT combined with acetic anhydride (1.27 mL). The reaction mixture isstirred for 1 h at RT. After the reaction has ended the solvent iseliminated using the rotary evaporator and the crude product (HPLC-MS:t_(Ret.)=0.81 min; MS (M+H)⁺=192) is used in subsequent reactionswithout further purification.

Preparation of the End Compounds

Example 264-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamidea)4-[4-((1R,2R)-2-amino-cyclopentyloxy)-5-trifluoromethyl-pyrimidin-2-ylamino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide

(R,R)-2-aminocyclopentanol×HCl (155 mg) is added to a suspension of NaH(135.2 mg) in dioxane (0.75 mL) and stirred for 30 min at RT. Then4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide(250 mg) is added. After 18 h, H₂O (50 mL) is added. The precipitateformed is filtered off, washed with H₂O, dissolved in CH₂Cl₂ andextracted with aqueous KHSO₄ solution (10%). The aqueous phase is madebasic again with K₂CO₃ and extracted with CH₂Cl₂. The organic phase isdried on magnesium sulphate, filtered to remove the desiccant and thesolvent is eliminated in vacuo.

b)4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclobentyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide

4-[4-((1R,2R)-2-amino-cyclopentyloxy)-5-trifluoromethyl-pyrimidin-2-ylamino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide(0.26 g) is dissolved in 4 mL CH₂Cl₂ and mixed with DIPEA (0.11 mL).Then methanesulphonyl chloride (0.05 mL) is added. The reaction mixtureis stirred for 18 h and purified by preparative HPLC without any furtherpre-purification. The product-containing fractions are combined andfreed from the solvent by freeze-drying.

Example 274-{4-[(1R,2R)-1-(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide

4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-15benzamide (50 mg) and N-((1R,2R)-2-amino-indan-1-yl)-methanesulphonamideN-((1R,2R)-2-hydroxy-indan-1-yl)-N-methyl-methanesulphonamide (54.4 mg)are suspended in dioxane (0.6 mL), mixed with Cs₂CO₃ (184 mg) as well assome MgSO₄ and stirred overnight at 85° C. The reaction mixture is leftto cool to RT, MeOH and isolate are added thereto and the solvent iseliminated using the rotary evaporator. Purification is carried out bypreparative HPLC.

Example 684-[4-((1R,2R)-1-acetylamino-indan-2-yloxy)-5-trifluoromethyl-pyrimidin-2-ylamino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide

N-((1R,2R)-2-hydroxy-indan-1-yl)-acetamide (43 mg) and4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide(50 mg) are suspended in 0.70 mL dioxane, mixed with Cs₂CO₃ (184 mg) andsome MgSO₄ and stirred overnight at 85° C. The reaction mixture isallowed to cool to RT and the solvent is eliminated using the rotaryevaporator. The residue is taken up in MeOH and purified by preparativeHPLC. The product-containing fractions are freeze-dried.

Analogously to the syntheses in Examples 26, 27 and 68 as describedabove, the following Examples in the Table and comparable additionalexamples may be obtained from the corresponding precursors, which areeither commercially obtainable or are obtained by methods known from theliterature.

TABLE 1 Examples 1-111 No. Structure MS (M + H)⁺ t_(Ret) [min] 1

600 2.05 2

641 2.12 3

640 2.38 4

678 1.99 5

696 2.03 6

584 2.05 7

790 2.26 8

655 2.16 9

624 2.24 10

668 2.03 11

668 2.02 12

626 1.82 13

660 1.92 14

623 1.85 15

622 2.07 16

678 1.77 17

566 1.76 18

772 2.00 19

650 1.70 20

637 2.11 21

606 2.12 22

650 1.97 23

635 1.96 24

653 2.01 25

667 2.10 26

587 1.80 27

649 1.99 28

605 1.89 29

679 1.94 30

621 1.87 31

697 2.08 32

649 1.98 33

532 1.88 34

678 1.92 35

660 1.87 36

626 1.77 37

580 2.02 38

582 1.50 39

622 2.20 40

623 1.94 41

637 2.02 42

626 1.77 43

566 1.69 44

619 2.05 45

639 2.05 46

631 2.04 47

655 1.92 48

647 1.96 49

626 1.82 50

626 1.82 51

610 1.83 52

644 1.91 53

607 2.06 54

564 2.02 55

634 1.97 56

608 1.80 57

662 1.98 58

756 2.22 59

634 1.88 60

621 2.18 61

606 1.77 62

649 1.97 63

650 1.85 64

644 1.88 65

644 1.87 66

590 2.31 67

550 2.06 68

599 1.83 69

649 2.00 70

649 1.99 71

635 1.85 72

599 1.84 73

588 1.66 74

649 1.93 75

633 1.98 76

615 1.90 77

616 1.76 78

595 1.87 79

649 1.95 80

650 1.82 81

623 1.96 82

637 2.01 83

472 1.82 84

601 1.84 85

585 1.89 86

643 1.98 87

669 2.06 88

586 1.73 89

602 1.72 90

649 2.35 91

649 2.04 92

649 2.12 93

635 1.85 94

566 1.94 95

609 1.90 96

627 2.02 97

474 1.82 98

606 1.73 99

579 2.02 100

636 1.85 101

620 1.81 102

635 1.89 103

619 2.04 104

601 1.82 105

619 1.90 106

593 1.92 107

659 1.48 108

609 1.86 109

623 1.96 110

607 2.00 111

589 1.90

The following Examples describe the biological activity of the compoundsaccording to the invention without restricting the invention to theseExamples.

PTK2 Enzyme Tests

Assay 1

This test uses active PTK2 enzyme (Invitrogen Code PV3832) andpoly-Glu-Tyr (4:1, Sigma P-0275) as the kinase substrate. The kinaseactivity is detected through the phosphorylation of the substrate in aDELFIA™ assay. The phosphorylated substrate is detected with theeuropium-labelled phosphotyrosine antibody PT60 (Perkin Elmer, No.:AD00400).

In order to determine concentration-activity curves with PTK2-inhibitorsthe compounds are serially diluted in 10% DMSO/H₂0 and 10 μL of eachdilution are placed in each well of a 96-well microtitre plate (clearplate with a U-shaped base, Greiner No. 650101) (the inhibitors aretested in duplicates) and mixed with 10 μL/well of PTK2 kinase (0.01μg/well). PTK2 kinase has been correspondingly diluted beforehand withkinase dilution buffer (20 mM TRIS/HCl pH 7.5, 0.1 mM EDTA, 0.1 mM EGTA,0.286 mM sodium orthovanadate, 10% glycerol with the addition of freshlyprepared BSA (fraction V, 1 mg/mL) and DTT (1 mM)). The test compoundand the PTK2 kinase are pre-incubated for 1 h at RT and shaken at 500revolutions per min. The reaction is started by the addition of 10μL/well poly (Glu,Tyr) substrate (25 μg/well poly (Glu, Tyr), 0.05μg/well biotinylated poly (Glu,Tyr) dissolved in 250 mM TRIS/HCl pH 7.5,9 mM DTT)—the final concentration of DMSO is 2%. Then 20 μL of ATP Mix(30 mM TRIS/HCl pH 7.5, 0.02% Brij, 0.2 mM sodium orthovanadate, 10 mMmagnesium acetate, 0.1 mM EGTA, 1× phosphatase inhibitor cocktail 1(Sigma, No.: P2850), 50 μM ATP (Sigma, No.: A3377; 15 mM stocksolution)) are added. After 1 h of kinase reaction (the plates areshaken at 500 rpm), the reaction is stopped by the addition of 12μL/well 100 mM EDTA, pH 8.0 and shaken for a further 5 min at RT (500rpm). 55 μL of the reaction mixture are transferred into a streptavidinplate (Strepta Well High Bind (transparent, 96-well) made by Roche, No.:11989685001) and incubated for 1 h at RT (shaking at 500 rpm). Then themicrotitre plate is washed three times with 200 μL/well D-PBS(Invitrogen, No. 14190). 100 μL of a solution containing DELFIA Eu-N1Anti-Phosphotyrosine PT60 antibody (Perkin Elmer, No.: AD0040, diluted1:2000 in DELFIA test buffer (Perkin Elmer, No.: 1244-111)) is thenadded and the mixture is incubated for 1 h at RT (shaking at 500 rpm).Then the plate is washed three times with 200 μL/well DELFIA washingbuffer (Perkin Elmer, No.: 1244-114), 200 μL/well strengthening solution(Perkin Elmer, No.: 1244-105) are added and the mixture is incubated for10 min at RT (shaking at 300 rpm).

The time-delayed europium fluorescence is then measured in a microtitreplate reader (VICTOR³, Perkin Elmer). The positive controls used arewells that contain the solvent controls (2% DMSO in test buffer) andexhibit uninhibited kinase activity. Wells that contain test bufferinstead of enzyme are used as a control of the background kinaseactivity.

The IC₅₀ values are determined from analyses of the concentrationactivity by iterative calculation with the aid of a sigmoid curveanalysis algorithm (FIFTY, based on GraphPAD Prism Version 3.03) with avariable Hill coefficient.

Assay 2

This test uses active PTK2 enzyme (Invitrogen Code PV3832) andpoly-Glu-Tyr (4:1, Sigma P-0275) as the kinase substrate. The kinaseactivity is detected by means of the phosphorylation of the substrate ina DELFIA™ assay. The phosphorylated substrate is detected with theeuropium-labelled phosphotyrosine antibody PT66 (Perkin Elmer, No.:AD0040).

In order to determine concentration-activity curves with PTK2-inhibitorsthe compounds are serially diluted first of all in 100% DMSO and then inkinase dilution buffer (20 mM TRIS/HCl pH 7.5, 0.1 mM EDTA, 0.1 mM EGTA,0.286 mM sodium orthovanadate, 10% glycerol with the addition of freshlyprepared BSA (fraction V, 1 mg/mL) and DTT (1 mM)) and 10 μL of eachdilution are dispensed per well in a 96-well microtitre plate (clearU-shaped base plate, Greiner No. 650101) (the inhibitors are tested induplicates) and mixed with 10 μL/well of PTK2 kinase (0.01 μg/well).PTK2 kinase is diluted accordingly beforehand with kinase dilutionbuffer. The diluted PTK2 inhibitor and the PTK2 kinase are pre-incubatedfor 1 h at RT and shaken at 500 revolutions per min. Then 10 μL/wellpoly-Glu-Tyr substrate (25 μg/well poly-Glu-Tyr, 0.05 μg/wellbiotinylated poly-Glu-Tyr dissolved in 250 mM TRIS/HCl pH 7.5, 9 mM DTT)are added. The reaction is started by the addition of 20 μL of ATP Mix(30 mM TRIS/HCl pH 7.5, 0.02% Brij, 0.2 mM sodium orthovanadate, 10 mMmagnesium acetate, 0.1 mM EGTA, 1× phosphatase inhibitor cocktail 1(Sigma, No.: P2850), 50 μM ATP (Sigma, No.: A3377; 15 mM stocksolution))—the final concentration of DMSO is 0.5%. After 1 h kinasereaction (the plates are shaken at 500 rpm), the reaction is stopped bythe addition of 12 μL/well of 100 mM EDTA, pH 8, and shaken for afurther 5 min at RT (500 U/min). 55 μL of the reaction mixture aretransferred into a streptavidin plate (Strepta Well High Bind(transparent, 96-well) made by Roche, No.: 11989685001) and incubatedfor 1 h at RT (shaking at 500 rpm). Then the microtitre plate is washedfive times with 200 μL/well D-PBS (Invitrogen, No. 14190). 100 μL of asolution containing DELFIA Eu-N1 Anti-Phosphotyrosine PT66 antibody(Perkin Elmer, No.: AD0040, diluted 1:9000 in DELFIA test buffer (PerkinElmer, No.: 1244-111)) is then added and it is incubated for 1 h at RT(shaking at 500 rpm). Then the plate is washed five times with 200μL/well DELFIA washing buffer (Perkin Elmer, No.: 1244-114), 200 μL/wellstrengthening solution (Perkin Elmer, No.: 1244-105) is added and thewhole is incubated for 10 min at RT (shaking at 300 rpm).

The time-delayed europium fluorescence is then measured in a microtitreplate reader (VICTOR³, Perkin Elmer). The positive control consists ofwells that contain solvent (0.5% DMSO in test buffer) and displayuninhibited kinase activity. Wells that contain test buffer instead ofenzyme act as a control for the background kinase activity.

The IC₅₀ values are determined from concentration-activity analyses byiterative calculation using a sigmoid curve analysis algorithm (FIFTY,based on GraphPAD Prism Version 3.03) with a variable Hill coefficient.

Table 2 that follows lists the IC₅₀ values of the example compoundsI—111 as obtained by determining from Assay 1 or Assay 2 (*). Theinhibitory effect of compounds according to the invention issufficiently demonstrated thereby.

TABLE 2 PTK2 1 h No. IC₅₀ [nM] 1 6 2 5 3 3 4 5 5 4 6 17 7 8 8 4 9 19 107 11 7 12 4 13 4 14 3 15 11 16 4 17 13 18 4 19 4 20 3 21 12 22 8 23 3 241 25 2 26 1 27 1 28 2 29 3 30 1 31 3 32 400 33 7 34 2 35 2 36 3 37 28 381 39 6 40 3 41 2 42 4 43 22 44 6 45 5 46 34 47 3 48 22 49 5 50 4 51 1352 6 53 4 54 92 55 6 56 9 57 2 58 6 59 6 60 3 61 4 62 3 63 3 64 6 65 1066 16 67 16 68 2 69 42 70 238 71 17 72 174 73 2 74 0.42 75 0.31 76 0.2977 0.3 78 0.37 79 0.4* 80 0.41 81 0.31 82 0.38 83 1 84 0.32 85 0.37 860.45 87 0.28 88 0.37 89 0.33 90 0.85* 91 4 92 3 93 0.42 94 5 95 0.56 960.54 97 2 98 4 99 0.37 100 0.26 101 0.3 102 0.61 103 0.28 104 0.32 1050.39 106 1 107 103 108 0.44 109 0.35 110 0.35 111 0.36Soft-Agar Assay

This cellular test is used to determine the influence of PTK2-inhibitorson the growth of PC-3 prostate carcinoma cells in soft agar(‘anchorage-independent growth’). After an incubation time of two weeksthe cell vitality is demonstrated by Alamar Blue (resazurin) staining.

PC-3 cells (ATCC CRL-1435) are grown in cell culture flasks (175 cm²)with F12 Kaighn's Medium (Gibco, No.: 21127) which has been supplementedwith 10% foetal calf serum (Invitrogen, No.: 16000-044). The culturesare incubated in the incubator at 37° C. and 5% CO₂ and are passagedtwice a week. The test is carried out in microtitre plates (Greiner,No.: 655 185) and consists of a lower layer made up of 90 μL of mediumwith 1.2% agarose (Invitrogen, 4% agarose gel 1×liquid 40 mL, No.:18300-012), followed by a cell layer in 60 μL medium and 0.3% agaroseand finally a top layer comprising 30 μL medium which contains the testcompounds (without the addition of agarose). To prepare the lower layer,4% agarose are decocted with 10×D-PBS (Gibco, No.: 14200) and H₂O andthus prediluted on 3% agarose in 1×D-PBS. The latter is adjusted withculture medium (F12 Kaighn's/10% FCS) and FCS to a final dilution of1.2% agarose in F12 Kaighn's Medium with 10% FCS. Each well of amicrotitre plate is supplied with 90 μL of the suspension for the lowerlayer and cooled to RT for 1 h. For the cell layer, PC-3 cells aredetached using trypsin (Gibco, 0.05%; No.: 25300), counted and seeded in60 μL F12 Kaighn's (10% FCS) with the addition of 0.3% agarose (37° C.).After cooling to RT for 1 h the test compounds (30 μL from serialdilutions) are added for quadruple measurements. The concentration ofthe test compounds usually covers a test range of between 10 μM and 0.3nM. The compounds (stock solution: 10 mM in 100% DMSO) are prediluted inF12 Kaighn's Medium+6% DMSO, to obtain a final concentration of 1% DMSO.The cells are incubated at 37° C. and 5% CO₂ in a steam-saturatedatmosphere for 14 days. The metabolic activity of living cells is thendemonstrated with the dye Alamar Blue (AbD Serotec, No.: BUF012B). To dothis, 18 μL/well of an Alamar Blue suspension are added and the whole isincubated for approx. 8 h in the incubator at 37° C. The positivecontrol consists of empty wells that are filled with a mixture of 18 μLof Alamar Blue reduced by autoclaving and 180 μL of F12 Kaighn's Medium(10% FCS). The fluorescence intensity is determined by means of afluorescence spectrometer (SpectraMAX GeminiXS, Molecular Devices). Theexcitation wavelength is 530 nm, the emission wavelength is 590 nm.

The EC₅₀ values are determined from concentrations-activity analyses byiterative calculation using a sigmoid curve analysis algorithm (FIFTY,based on GraphPAD Prism Version 3.03) with a variable Hill coefficient.

Phospho-PTK2 (pY397) Assay

This cellular test is used to determine the influence of PTK2-inhibitorson the state of the PTK2-phosphorylation at tyrosine 397 (pY397).

PC-3 cells (prostate carcinoma, ATCC CRL-1435) are grown in cell cultureflasks (175 cm²) with F12 Kaighn's Medium (Gibco, No.: 21127) with theaddition of 10% foetal calf serum (Invitrogen, No.: 16000-044). Thecultures are incubated in the incubator at 37° C. and 5% CO₂ andpassaged twice a week.

For the test, 2×10⁴ cells pro well/90 μL medium are plated out in96-well microtitre plates (Costar, No.: 3598) and incubated overnight inthe incubator at 37° C. and 5% CO₂. The test compounds (10 μL fromserial dilution) are added the next day. The concentration of the testcompounds usually covers a range of 50 μM and 0.8 nM. The test compounds(stock solution: 10 mM in 100% DMSO) are diluted in medium/medium 10%DMSO such that the final concentration is 1% DMSO. The cells are thenincubated in the incubator at 37° C. and 5% CO₂ for 2 h. Then theculture supernatant is removed and the cells are fixed with 150 μL 4%formaldehyde in D-PBS for 20 min at RT. (The cell lawn is washed fivetimes with 200 μl of 0.1% Triton X-100 in D-PBS) for 5 min each time andthen incubated for 90 minutes with blocking buffer (5% skimmed milkpowder (Maresi Fixmilch) in TBST (25 mM Tris/HCl, pH 8.0, 150 mM NaCl,0.05% Tween 20). The blocking buffer is replaced by 50 μL of the firstantibody anti-phospho PTK2 [pY397] rabbit monoclonal(Invitrogen/Biosource, No.: 44-625G), which is diluted 1:200 in blockingbuffer. For control purposes, alternatively a PTK2 [total] antibody(clone 4.47 mouse monoclonal, Upstate, No.: 05-537), diluted 1:400 inblocking buffer is used. This incubation is carried out at 4° C.overnight. Then the cell lawn is washed five times with 100 μl 0.1%Tween in D-PBS for 5 min in each case and 50 μL/well of second antibodyare added. In order to detect bound phospho-PTK2 [pY397] antibody agoat-anti-rabbit antibody is used which is coupled with horseradishperoxidase (Dako, No.: P0448; 1:500 dilution in blocking buffer). Inorder to detect bound PTK2 [total]-antibodies a rabbit-anti-mouseantibody is used, which is also coupled with horseradish peroxidase(Dako, No.: PO161; 1:1000 dilution in blocking buffer). This incubationis carried out for 1 h at RT with gentle shaking. The cell lawn is thenagain washed five times with 100 μl of 0.1% Tween in D-PBS for 5 min ineach case. Peroxidase staining is carried out by adding 100 μL stainingsolution (1:1 mixture of TMB peroxidase substrate (KPL, No.: 50-76-02)and peroxidase solution B (H₂O₂) (KPL, No.: 50-65-02). The developmentof the stain takes place for 10 to 30 min in the dark. The reaction isstopped by the addition of 100 μL/well of a 1 M phosphoric acidsolution. The absorption is determined photometrically at 450 nm with anabsorption measuring device (VICTOR³PerkinElmer). The inhibition of theanti-phospho PTK2 [pY397] immune staining is used to determine EC₅₀values. The staining with anti-PTK2 [total]-antibodies is for controlpurposes and should remain constant under the influence of inhibitor.The EC₅₀ values are determined from concentration-activity analyses byiterative calculation with the aid of a sigmoid curve analysis algorithm(FIFTY, based on GraphPAD Prism Version 3.03) with a variable Hillcoefficient.

Example compounds 1-100 have an EC₅₀ value (PC-3) of less than 10 μM,generally less than 1 μM.

The substances of the present invention are PTK2 kinase inhibitors. Inview of their biological properties the new compounds of general formula(1a) or (1b), the isomers thereof and the physiologically acceptablesalts thereof are suitable for the treatment of diseases characterisedby excessive or abnormal cell proliferation.

Such diseases include for example: viral infections (e.g. HIV andKaposi's sarcoma); inflammatory and autoimmune diseases (e.g. colitis,arthritis, Alzheimer's disease, glomerulonephritis and wound healing);bacterial, fungal and/or parasitic infections; leukaemias, lymphomas andsolid tumours (e.g. carcinomas and sarcomas), skin diseases (e.g.psoriasis); diseases based on hyperplasia which are characterised by anincrease in the number of cells (e.g. fibroblasts, hepatocytes, bonesand bone marrow cells, cartilage or smooth muscle cells or epithelialcells (e.g. endometrial hyperplasia)); bone diseases and cardiovasculardiseases (e.g. restenosis and hypertrophy).

For example, the following cancers may be treated with compoundsaccording to the invention, without being restricted thereto:

brain tumours such as for example acoustic neurinoma, astrocytomas suchas fibrillary, protoplasmic, gemistocytary, anaplastic, pilocyticastrocytomas, glioblastoma, gliosarcoma, pleomorphic xanthoastrocytoma,subependymal large-cell giant cell astrocytoma and desmoplasticinfantile astrocytoma; brain lymphomas, brain metastases, hypophysealtumour such as prolactinoma, hypophyseal incidentaloma, HGH (humangrowth hormone) producing adenoma and corticotrophic adenoma,craniopharyngiomas, medulloblastoma, meningeoma and oligodendroglioma;nerve tumours such as for example tumours of the vegetative nervoussystem such as neuroblastoma, ganglioneuroma, paraganglioma(pheochromocytoma, chromaffinoma) and glomus-caroticum tumour, tumourson the peripheral nervous system such as amputation neuroma,neurofibroma, neurinoma (neurilemmoma, Schwannoma) and malignantSchwannoma, as well as tumours of the central nervous system such asbrain and bone marrow tumours; intestinal cancer such as for examplecarcinoma of the rectum, colon, anus and duodenum; eyelid tumours(basalioma or adenocarcinoma of the eyelid apparatus); retinoblastoma;carcinoma of the pancreas; carcinoma of the bladder; lung tumours(bronchial carcinoma—small-cell lung cancer (SCLC), non-small-cell lungcancer (NSCLC) such as for example spindle-cell plate epithelialcarcinomas, adenocarcinomas (acinary, paillary, bronchiolo-alveolar) andlarge-cell bronchial carcinoma (giant cell carcinoma, clear-cellcarcinoma); breast cancer such as ductal, lobular, mucinous or tubularcarcinoma, Paget's carcinoma; non-Hodgkin's lymphomas (B-lymphatic orT-lymphatic NHL) such as for example hair cell leukaemia, Burkitt'slymphoma or mucosis fungoides; Hodgkin's disease; uterine cancer (corpuscarcinoma or endometrial carcinoma); CUP syndrome (Cancer of UnknownPrimary); ovarian cancer (ovarian carcinoma—mucinous or serous cystoma,endometriodal tumours, clear cell tumour, Brenner's tumour); gallbladder cancer; bile duct cancer such as for example Klatskin tumour;testicular cancer (germinal or non-germinal germ cell tumours);laryngeal cancer such as for example supra-glottal, glottal andsubglottal tumours of the vocal cords; bone cancer such as for exampleosteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma,chondrosarcoma, osteoma, osteoid osteoma, osteoblastoma, osteosarcoma,non-ossifying bone fibroma, osteofibroma, desmoplastic bone fibroma,bone fibrosarcoma, malignant fibrous histiocyoma, osteoclastoma or giantcell tumour, Ewing's sarcoma, and plasmocytoma, head and neck tumours(HNO tumours) such as for example tumours of the lips, and oral cavity(carcinoma of the lips, tongue, oral cavity), nasopharyngeal carcinoma(tumours of the nose, lymphoepithelioma), pharyngeal carcinoma,oropharyngeal carcinomas, carcinomas of the tonsils (tonsil malignoma)and (base of the) tongue, hypopharyngeal carcinoma, laryngeal carcinoma(cancer of the larynx), tumours of the paranasal sinuses and nasalcavity, tumours of the salivary glands and ears; liver cell carcinoma(hepatocellular carcinoma (HCC); leukaemias, such as for example acuteleukaemias such as acute lymphatic/lymphoblastic leukaemia (ALL), acutemyeloid leukaemia (AML); chronic lymphatic leukaemia (CLL), chronicmyeloid leukaemia (CML); stomach cancer (papillary, tubular or mucinousadenocarcinoma, adenosquamous, squamous or undifferentiated carcinoma);malignant melanomas such as for example superficially spreading (SSM),nodular (NMM), lentigo-maligna (LMM), acral-lentiginous (ALM) oramelanotic melanoma (AMM); renal cancer such as for example kidney cellcarcinoma (hypernephroma or Grawitz's tumour); oesophageal cancer;penile cancer; prostate cancer; vaginal tumors (vaginal carcinoma orcervical carcinoma); thyroid carcinomas such as for example papillary,follicular, medullary or anaplastic thyroid carcinoma; thymus carcinoma(thymoma); cancer of the urethra (carcinoma of the urethra, urothelialcarcinoma) and vulvar carcinoma.

The new compounds may be used for the prevention, short-term orlong-term treatment of the above-mentioned diseases, optionally also incombination with radiotherapy or other “state-of-the-art” compounds,such as e.g. cytostatic or cytotoxic substances, cell proliferationinhibitors, anti-angiogenic substances, steroids or antibodies.

The compounds of general formula (1a) and (1b) may be used on their ownor in combination with other active substances according to theinvention, optionally also in combination with other pharmacologicallyactive substances.

Chemotherapeutic agents which may be administered in combination withthe compounds according to the invention include, without beingrestricted thereto, hormones, hormone analogues and antihormones (e.g.tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate,flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproteroneacetate, finasteride, buserelin acetate, fludrocortisone,fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors(e.g. anastrozole, letrozole, liarozole, vorozole, exemestane,atamestane), LHRH agonists and antagonists (e.g. goserelin acetate,luprolide), inhibitors of growth factors (growth factors such as forexample “platelet derived growth factor” and “hepatocyte growth factor”,inhibitors are for example “growth factor” antibodies, “growth factorreceptor” antibodies and tyrosinekinase inhibitors, such as for examplegefitinib, lapatinib and trastuzumab); signal transduction inhibitors(e.g. Imatinib and sorafenib); antimetabolites (e.g. antifolates such asmethotrexate, premetrexed and raltitrexed, pyrimidine analogues such as5-fluorouracil, capecitabin and gemcitabin, purine and adenosineanalogues such as mercaptopurine, thioguanine, cladribine andpentostatin, cytarabine, fludarabine); antitumour antibiotics (e.g.anthracyclins such as doxorubicin, daunorubicin, epirubicin andidarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin,streptozocin); platinum derivatives (e.g. cisplatin, oxaliplatin,carboplatin); alkylation agents (e.g. estramustin, meclorethamine,melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide,ifosfamide, temozolomide, nitrosoureas such as for example carmustin andlomustin, thiotepa); antimitotic agents (e.g. Vinca alkaloids such asfor example vinblastine, vindesin, vinorelbin and vincristine; andtaxanes such as paclitaxel, docetaxel); topoisomerase inhibitors (e.g.epipodophyllotoxins such as for example etoposide and etopophos,teniposide, amsacrin, topotecan, irinotecan, mitoxantron) and variouschemotherapeutic agents such as amifostin, anagrelid, clodronat,filgrastin, interferon alpha, leucovorin, rituximab, procarbazine,levamisole, mesna, mitotane, pamidronate and porfimer.

Other possible combination partners are 2-chlorodesoxyadenosine,2-fluorodesoxy-cytidine, 2-methoxyoestradiol, 2C4,3-alethin,131-I-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-azaepothilon B, A105972, A 204197, aldesleukin, alitretinoin, altretamin, alvocidib,amonafid, anthrapyrazole, AG-2037, AP-5280, apaziquon, apomin, aranose,arglabin, arzoxifen, atamestan, atrasentan, auristatin PE, AVLB,AZ10992, ABX-EGF, ARRY-300, ARRY-142886/AZD-6244, ARRY-704/AZD-8330,AS-703026, azacytidin, azaepothilon B, azonafid, BAY-43-9006, BBR-3464,BBR-3576, bevacizumab, biricodar dicitrate, BCX-1777, bleocin, BLP-25,BMS-184476, BMS-247550, BMS-188797, BMS-275291, BNP-1350, BNP-7787, BIBW2992, BIBF 1120, bleomycinic acid, bleomycin A, bleomycin B,bryostatin-1, bortezomib, brostallicin, busulphan, CA-4 prodrug, CA-4,CapCell, calcitriol, canertinib, canfosfamid, capecitabin,carboxyphthalatoplatin, CCI-779, CEP-701, CEP-751, CBT-1cefixim,ceflatonin, ceftriaxon, celecoxib, celmoleukin, cemadotin,CH4987655/RO-4987655, chlorotrianisen, cilengitid, ciclosporin, CDA-II,CDC-394, CKD-602, clofarabin, colchicin, combretastatin A4, CHS-828,CLL-Thera, CMT-3cryptophycin 52, CTP-37, CP-461, CV-247,cyanomorpholinodoxorubicin, cytarabin, D 24851, decitabin, deoxorubicin,deoxyrubicin, deoxycoformycin, depsipeptid, desoxyepothilon B,dexamethasone, dexrazoxanet, diethylstilbestrol, diflomotecan, didox,DMDC, dolastatin 10, doranidazole, E7010, E-6201, edatrexat, edotreotid,efaproxiral, eflornithin, EKB-569, EKB-509, elsamitrucin, epothilon B,epratuzumab, ER-86526, erlotinib, ET-18-OCH3, ethynylcytidin,ethynyloestradiol, exatecan, exatecan mesylate, exemestan, exisulind,fenretinid, floxuridin, folic acid, FOLFOX, FOLFIRI, formestan,galarubicin, gallium maltolate, gefinitib, gemtuzumab, gimatecan,glufosfamid, GCS-100, G17DT immunogen, GMK, GPX-100, GSK-5126766,GSK-1120212, GW2016, granisetron, hexamethylmelaminr, histamine,homoharringtonin, hyaluronic acid, hydroxyurea, hydroxyprogesteronecaproate, ibandronat, ibritumomab, idatrexat, idenestrol, IDN-5109,IMC-1C11, immunol, indisulam, interferon alpha-2a, interferon alfa-2b,interleukin-2, ionafarnib, iproplatin, irofulven, isohomohalichondrin-B,isoflavone, isotretinoin, ixabepilon, JRX-2, JSF-154, J-107088,conjugated oestrogens, Kahalid F, ketoconazole, KW-2170, lobaplatin,leflunomid, lenograstim, leuprolid, leuporelin, lexidronam, LGD-1550,linezolid, lutetium-texaphyrin, lometrexol, losoxantron, LU 223651,lurtotecan, mafosfamid, marimastat, mechloroethamin, methyltestosterone,methylprednisolone, MEN-10755, MDX-H210, MDX-447, MGV, midostaurin,minodronic acid, mitomycin, mivobulin, MK-2206, MLN518,motexafin-gadolinium, MS-209, MS-275, MX6, neridronat, neovastat,nimesulid, nitroglycerine, nolatrexed, norelin, N-acetylcysteine,06-benzylguanine, omeprazole, oncophage, ormiplatin, ortataxel,oxantrazole, oestrogen, patupilon, pegfilgrastim, PCK-3145,PEG-filgrastim, PBI-1402, PEG-paclitaxel, PEP-005, P-04, PKC412, P54,P1-88, pelitinib, pemetrexed, pentrix, perifosin, perillylalcohol,PG-TXL, PG2, PLX-4032/RO-5185426, PT-100, picoplatin,pivaloyloxymethylbutyrate, pixantron, phenoxodiol 0, PKI166,plevitrexed, plicamycin, polyphonic acid, porfiromycin, prednisone,prednisolone, quinamed, quinupristin, RAF-265, ramosetron, ranpirnase,RDEA-119/BAY 869766, rebeccamycin analogues, revimid, RG-7167, rhizoxin,rhu-mab, risedronat, rituximab, rofecoxib, RO-31-7453, RO-5126766, RPR109881A, rubidazon, rubitecan, R-flurbiprofen, S-9788, sabarubicin,SAHA, sargramostim, satraplatin, SB 408075, SU5416, SU6668, SDX-101,semustin, seocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747,SRL-172, sorafenib, spiroplatin, squalamin, suberanilohydroxamic acid,sutent, T 900607, T 138067, TAS-103, tacedinalin, talaporfin,tariquitar, taxotere, taxoprexin, tazaroten, tegafur, temozolamid,tesmilifen, testosterone, testosterone propionate, tetraplatin,tetrodotoxin, tezacitabine, thalidomide, theralux, therarubicin,thymectacin, tiazofurin, tipifarnib, tirapazamine, tocladesin, tomudex,toremofin, trabectedin, transMID-107, transretinoic acid, traszutumab,tretinoin, triacetyluridine, triapin, trimetrexate, TLK-286TXD 258,urocidin, valrubicin, vatalanib, vincristin, vinflunin, virulizin,WX-UK1, vectibix, xeloda, XELOX, XL-281, XL-518/R-7420, YM-511, YM-598,ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZD1839,zoledronate and zosuquidar.

Suitable preparations include for example tablets, capsules,suppositories, solutions, —particularly solutions for injection (s.c.,i.v., i.m.) and infusion—syrups, elixirs, emulsions or dispersiblepowders. The content of the pharmaceutically active compound(s) shouldbe in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of thecomposition as a whole, i.e. In amounts which are sufficient to achievethe dosage range specified below. The doses specified may, if necessary,be given several times a day.

Suitable tablets may be obtained, for example, by mixing the activesubstance(s) with known excipients, for example inert diluents such ascalcium carbonate, calcium phosphate or lactose, disintegrants such ascorn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc and/or agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidine or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances or combinationsthereof according to the invention may additionally contain a sweetenersuch as saccharine, cyclamate, glycerol or sugar and a flavour enhancer,e.g. a flavouring such as vanillin or orange extract. They may alsocontain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions for injection and infusion are prepared in the usual way, e.g.with the addition of isotonic agents, preservatives such asp-hydroxybenzoates, or stabilisers such as alkali metal salts ofethylenediamine tetraacetic acid, optionally using emulsifiers and/ordispersants, whilst if water is used as the diluent, for example,organic solvents may optionally be used as solvating agents ordissolving aids, and transferred into injection vials or ampoules orinfusion bottles.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

The preparations are administered by the usual methods, preferably byoral or transdermal route, most preferably by oral route. For oraladministration the tablets may, of course contain, apart from theabovementioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

For parenteral use, solutions of the active substances with suitableliquid carriers may be used.

The dosage for intravenous use is from 1-1000 mg per hour, preferablybetween 5 and 500 mg per hour.

However, it may sometimes be necessary to depart from the amountsspecified, depending on the body weight, the route of administration,the individual response to the drug, the nature of its formulation andthe time or interval over which the drug is administered. Thus, in somecases it may be sufficient to use less than the minimum dose givenabove, whereas in other cases the upper limit may have to be exceeded.When administering large amounts it may be advisable to divide them upinto a number of smaller doses spread over the day.

The formulation examples that follow illustrate the present inventionwithout restricting its scope:

Examples of Pharmaceutical Formulations

A) Tablets per tablet active substance according to formula (1a)(1b) 100mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone  15 mgmagnesium stearate  5 mg 500 mg

The finely ground active substance, lactose and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size.

B) Tablets per tablet active substance according to formula (1a)(1b) 80mg lactose 55 mg corn starch 190 mg  microcrystalline cellulose 35 mgpolyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesiumstearate  2 mg 400 mg 

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. Thesodiumcarboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize.

C) Ampoule solution active substance according to formula (1a)(1b) 50 mgsodium chloride 50 mg water for inj.  5 ml

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50mg of active substance.

The invention claimed is:
 1. A compound of formula (1a) or (1b)

wherein A denotes a group, optionally substituted by one or more,identical or different R², selected from among C₃₋₁₀cycloalkyl, 3-8membered heterocycloalkyl, C₆₋₁₅aryl and 5-12-membered heteroaryl; Qdenotes a group, optionally substituted by one or more, identical ordifferent R⁴, selected from among phenyl and 56 membered heteroaryl; R¹denotes a group selected from among halogen, —OR^(c), —OCF₃, —SR^(c),—NR^(c)R^(c), —CF₃, —CN, —OCN, —SCN, —NO, —NO₂, C₁₋₃alkyl, C₁₋₃haloalkyland C₁₋₃haloalkyloxy; R², R⁴ and R⁵ each independently of one anotherdenote hydrogen or a group selected from among R^(a), R^(b) and R^(a)substituted by one or more, identical or different R^(c) and/or R^(b);R³ denotes a group selected from among —OS(O)R^(c), —OS(O)₂R^(c),—OS(O)₂R^(c), —OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c), —OC(O)R^(c),—OC(O)OR^(c), —OC(O)SR^(c), —OC(O)NR^(c)R^(c), —SC(O)R^(c),—SC(O)OR^(c), —SC(O)NR^(c)R^(c), —N(R^(g))C(O)R^(c), —N[C(O)R^(c)]₂,—N(OR^(g))C(O)R^(c), —N[C(O)R^(c)]NR^(c)R^(c), —N(R^(g))S(O)R^(c),—N(R^(g))S(O)OR^(c), —N(R^(g))S(O)₂R^(c), —N[S(O)₂R^(c)[₂,—N(R^(g))S(O)₂OR^(c), —N(R^(g))S(O)₂NR^(c)R^(c), —N(R^(g))[S(O)₂]₂R^(c),—N(R^(g))C(O)OR^(c), —N(R^(g))C(O)SR^(c), —N(R^(g))C(O)NR^(c)R^(c),—N(R^(g))C(O)NR^(g)NR^(c)R^(c), —[N(R^(g))C(O)]₂R^(c),—N(R^(g))[C(O)]₂R^(c), —N{[C(O)]₂R^(c)}₂, —N(R^(g))[C(O)]₂OR^(c),—N(R^(g))[C(O)]₂NR^(c)R^(c), —N{[C(O)]₂OR^(c)}₂, —N{[C(O)]₂NR^(c)R^(c)}₂and —[N(R^(g))C(O)]₂OR^(c); each R^(a) is independently selected fromamong C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₄₋₁₆cycloalkylalkyl, C₆₋₁₀aryl,C₇₋₁₆arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocycloalkyl,4-14 membered heterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18membered heteroarylalkyl; each R^(b) is a suitable group and each isindependently selected from among ═O, —OR^(c), C₁₋₃haloalkyloxy, —OCF₃,═S, —SR^(c), ═NR^(c), ═NOR^(c), ═NNR^(c)R^(c),═NN(R^(g))C(O)NR^(c)R^(c), —NR^(c)R^(c), —ONR^(c)R^(c), —N(OR^(c))R^(c),—N(R^(g))NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂,═N₂, —N₃, —S(O)R^(c), —S(O)OR^(c), —S(O)₂R^(c), —S(O)₂OR^(c),—S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(c), —OS(O)₂R^(c),—OS(O)₂OR^(c), —OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c), —C(O)R^(c),—C(O)OR^(c), —C(O)SR^(c), —C(O)NR^(c)R^(c), —C(O)N(R^(g))NR^(c)R^(c),—C(O)N(R^(g))OR^(c), —C(NR^(g))NR^(c)R^(c), —C(NOH)R^(c),—C(NOH)NR^(c)R^(c), —OC(O)R^(c), —OC(O)OR^(c), —OC(O)SR^(c),—OC(O)NR^(c)R^(c), —OC(NR^(g))NR^(c)R^(c), —SC(O)R^(c), —SC(O)OR^(c),—SC(O)NR^(c)R^(c), —SC(NR^(g))NR^(c)R^(c), —N(R^(g))C(O)R^(c),—N[C(O)R^(c)]₂, —N(OR^(g))C(O)R^(c), —N(R^(g))C(NR^(g))R^(c),—N(R^(g))N(R^(g))C(O)R^(c), —N[C(O)R^(c)]NR^(c)R^(c),—N(R^(g))C(S)R^(c), —N(R^(g))S(O)R^(c), —N(R^(g))S(O)OR^(c),—N(R^(g))S(O)₂R^(c), —N[S(O)₂R^(c)]₂, —N(R^(g))S(O)₂OR^(c),—N(R^(g))S(O)₂NR^(c)R^(c), —N(R^(g))[S(O)₂]₂R^(c), —N(R^(g))C(O)OR^(c),—N(R^(g))C(O)SR^(c), —N(R^(g))C(O)NR^(c)R^(c),—N(R^(g))C(O)NR^(g)NR^(c)R^(c), —N(R^(g))N(R^(g))C(O)NR^(c)R^(c),—N(R^(g))C(S)NR^(c)R^(c), —[N(R^(g))C(O)]₂R^(c), —N(R^(g))[C(O)]₂R^(c),—N{[C(O)]₂R^(c)}₂, —N(R^(g))[C(O)]₂OR^(c), —N(R^(g))[C(O)]₂NR^(c)R^(c),—N{[C(O)]₂OR^(c)}₂, —N{[C(O)]₂NR^(c)R^(c)}₂, —[N(R^(g))C(O)]₂OR^(c),—N(R^(g))C(NR^(g))OR^(c), —N(R^(g))C(NOH)R^(c), —N(R^(g))C(NR^(g))SR^(c)and —N(R^(g))C(NR^(g))NR^(c)R^(c); each R^(b) independently denoteshydrogen or a group optionally substituted by one or more, identical ordifferent R^(d) and/or R^(e) selected from among C₁₋₆alkyl,C₃₋₁₀cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 memberedheterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 memberedheteroarylalkyl; each R^(d) is a suitable group and each isindependently selected from among ═O, —OR^(e), C₁₋₃haloalkyloxy, —OCF₃,═S, —SR^(e), ═NR^(e), ═NOR^(e), ═NNR^(e)R^(e),═NN(R^(g))C(O)NR^(e)R^(e), —NR^(e)R^(e), —ONR^(e)R^(e),—N(R^(g))NR^(e)R^(e), halogen, —CF₃, —CN, —NC, —OCN, —SCN, —NO, —NO₂,═N₂, —N₃, —S(O)R^(e), —S(O)OR^(e), —S(O)₂R^(e), —S(O)₂OR^(e),—S(O)NR^(e)R^(e), —S(O)₂NR^(e)R^(e), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)₂OR^(e), —OS(O)NR^(e)R^(e), —OS(O)₂NR^(e)R^(e), —C(O)R^(e),—C(O)OR^(e), —C(O)SR^(e), —C(O)NR^(e)R^(e), —C(O)N(R^(g))NR^(e)R^(e),—C(O)N(R^(g))OR^(e), —C(NR^(g))NR^(e)R^(e), —C(NOH)R^(e),—C(NOH)NR^(e)R^(e), —OC(O)R^(e), —OC(O)OR^(e), —OC(O)SR^(e),—OC(O)NR^(e)R^(e), —OC(NR^(g))NR^(e)R^(e), —SC(O)R^(e), —SC(O)OR^(e),—SC(O)NR^(e)R^(e), —SC(NR^(g))NR^(e)R^(e), —N(R^(g))C(O)R^(e),—N[C(O)R^(e)]₂, —N(OR^(g))C(O)R^(e), —N(R^(g))C(NR^(g))R^(e),—N(R^(g))N(R^(g))C(O)R^(e), —N[C(O)R^(e)]NR^(e)R^(e),—N(R^(g))C(S)R^(e), —N(R^(g))S(O)R^(e), —N(R^(g))S(O)OR^(e),—N(R^(g))S(O)₂R^(e), —N[S(O)₂R^(e)]₂, —N(R^(g))S(O)₂OR^(e),—N(R^(g))S(O)₂NR^(e)R^(e), —N(R^(g))[S(O)₂]₂R^(e), —N(R^(g))C(O)OR^(e),—N(R^(g))C(O)SR^(e), —N(R^(g))C(O)NR^(e)R^(e),—N(R^(g))C(O)NR^(g)NR^(e)R^(e), —N(R^(g))N(R^(g))C(O)NR^(e)R^(e),—N(R^(g))C(S)NR^(e)R^(e), —[N(R^(g))C(O)]₂R^(e), —N(R^(g))[C(O)]₂R^(e),—N{[C(O)]₂R^(e)}₂, —N(R^(g))[C(O)]₂OR^(e), —N(R^(g))[C(O)]₂NR^(e)R^(e),—N{[C(O)]₂OR^(e)}₂, —N{[C(O)]₂NR^(e)R^(e)}₂, —[N(R^(g))C(O)]₂OR^(e),—N(R^(g))C(NR^(g))OR^(e), —N(R^(g))C(NOH)R^(e), —N(R^(g))C(NR^(g))SR^(e)and —N(R^(g))C(NR^(g))NR^(e)R^(e); each R^(e) independently denoteshydrogen or a group optionally substituted by one or more, identical ordifferent R^(f) and/or R^(g) selected from among C₁₋₆alkyl,C₃₋₈cycloalkyl, C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6membered heteroalkyl, 3-8 membered heterocycloalkyl, 4-14 memberedheterocycloalkylalkyl, 5-12 membered heteroaryl and 6-18 memberedheteroarylalkyl; each R^(f) is a suitable group and each isindependently selected from among halogen and —CF₃; each R^(g)independently denotes hydrogen, C₁₋₆alkyl, C₃₋₈cycloalkyl,C₄₋₁₁cycloalkylalkyl, C₆₋₁₀aryl, C₇₋₁₆arylalkyl, 2-6 memberedheteroalkyl, 3-8 membered heterocycloalkyl, 4-14 memberedheterocycloalkyl, 5-12 membered heteroaryl or 6-18 memberedheteroarylalkyl; m and p independently of one another denote 0, 1, 2 or3 and n and q denote 0, 1, 2 or 3; a tautomer thereof, a racematethereof, an enantiomer thereof, a diastereomer thereof or a mixture ofany of the foregoing, or a salt thereof.
 2. The compound of formula (1a)according to claim 1

wherein R¹, R², R³, R⁴, A, Q, n and m are defined as in claim
 1. 3. Thecompound according to claim 2, wherein n is
 1. 4. The compound accordingto claim 1, wherein m is equal to
 0. 5. The compound of formula (1 b)according to claim 1

wherein R¹, R², R³, R⁵, A, p and q are defined as in claim
 1. 6. Thecompound according to claim 5, wherein q is equal to 1 or
 2. 7. Thecompound according to claim 5, wherein p is equal to
 0. 8. The compoundaccording to claim 1, wherein R³ is selected from among—N(R^(g))C(O)R^(c), —N(OR^(g))C(O)R^(c), —N(R^(g))S(O)₂R^(c),—N(R^(g))C(O)OR^(c) and —N(R^(g))C(O)NR^(c)R^(c) and R^(c) and R^(g) aredefined as in claim
 1. 9. The compound according to claim 1, wherein thegroup

denotes

R⁶ and R⁷ are defined as R² in claim 1, r is equal to 1 or 2 and A isdefined as in claim
 1. 10. The compound according to claim 9, wherein Ais a group selected from among phenyl and 5-10 membered heteroaryl andR⁶, R⁷ and r are defined as in claim
 9. 11. The compound according toclaim 10, wherein A is a phenyl; r has the value 1 or 2; and each R⁷ isindependently selected from among halogen, C₁₋₆alkyl and C₁₋₆alkoxy. 12.The compound according to claim 9, wherein R⁶ is selected from amonghydrogen, R^(a2), R^(b2) and R^(a2) substituted by one or more,identical or different R^(b2) and/or R^(c2); each R^(a2) isindependently selected from among C₁₋₆alkyl and 3-7 memberedheterocycloalkyl; each R^(b2) is a suitable substituent and isindependently selected from among O═, —OR^(c2), —NR^(c2)R^(c2),—C(O)R^(c2), —C(O)OR^(c2), —C(O)NR^(c2)R^(c2), —C(O)N(R^(g2))OR^(c2),—N(R^(g2))C(O)R^(c2), -vN(R^(g2))C(O)OR^(c2) and—N(R^(g2))C(O)NR^(c2)R^(c2), each R^(c2) independently denotes hydrogenor a group optionally substituted by one or more, identical or differentR^(d2) and/or R^(e2), selected from among C₁₋₆alkyl, C₃₋₆cycloalkyl and3-7 membered heterocycloalkyl; each R^(d2) is a suitable substituent andis independently selected from among —OR^(e2), —NR^(e2)R^(e2),—C(O)N(R^(g2))OR^(e2) and —C(O)NR^(e2)R^(e2); each R^(e2) independentlydenotes hydrogen or a group optionally substituted by one or more,identical or different R^(f2) and/or R^(g2), selected from amongC₁₋₆alkyl, C₃₋₆cycloalkyl, 5-6 membered heteroaryl and 3-7 memberedheterocycloalkyl; each R^(f2) independently denotes —OR^(g2) and eachR^(g2) is independently selected from among hydrogen, C₁₋₆alkyl andC₄₋₉cycloalkylalkyl.
 13. The compound according to claim 1 selected fromthe group consisting of:4-[4-((1R,2R)-1-methanesulphonylamino-indan-2-yloxy)-5-trifluoromethyl-pyrimidin-2-ylamino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;2-fluoro-4-[4-((1R,2R)-1-methanesulphonylamino-indan-2-yloxy)-5-trifluoromethyl-pyrimidin-2-ylamino]-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;2-fluoro-4-{4-[(1R,2R)-1-(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;4-{4-[(1R,2R)-1-(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;2-fluoro-4-[4-((1R,2R)-2-methanesulphonylamino-cyclopentyloxy)-5-trifluoromethyl-pyrimidin-2-ylamino]-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;4-{4-[(1R,2R)-1-(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-3-methoxy-N-((3S,4S)-3-methoxy-1-methyl-piperidin-4-yl)-benzamide;2-fluoro-4-{4-[(1R,2R)-1-(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-((3S,4S)-3-methoxy-1-methyl-piperidin-4-yl)-benzamide;2-chloro-4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclohexyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;2-fluoro-4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclohexyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclohexyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-3-methoxy-N-(4-methyl-piperazin-1-yl)-benzamide;3-{4-[(1R,2R)-1-(methanesulphonyl-methyl-amino)-indan-2-yloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-4-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;2-chloro-4-{5-chloro-4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-pyrimidin-2-ylamino}-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;4-{5-chloro-4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-pyrimidin-2-ylamino}-2-fluoro-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;4-{5-chloro-4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-pyrimidin-2-ylamino}-2-fluoro-5-methoxy-N-(4-methyl-piperazin-1-yl)-benzamide;N-((1R,2R)-2-{2-[4-(4-tert-butyl-piperazin-1-yl)-2-methoxy-phenylamino]-5-trifluoromethyl-pyrimidin-4-yloxy}-indan-1-yl)-N-methyl-methanesulphonamid;2-chloro-4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(4-methyl-piperazin-1-yl)-benzamide;2-fluoro-4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(4-methyl-piperazin-1-yl)-benzamide;2-chloro-4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;2-fluoro-4-{4-[(1R,2R)-2-(methanesulphonyl-methyl-amino)-cyclopentyloxy]-5-trifluoromethyl-pyrimidin-2-ylamino}-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide;2-fluoro-4-[4-((1R,2R)-2-methanesulphonylamino-cyclohexyloxy)-5-trifluoromethyl-pyrimidin-2-ylamino]-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamideand a tautomer or salt of any of the foregoing compounds.
 14. A methodfor treating prostate cancer in a warm-blooded animal comprisingadministering to said animal a therapeutically effective amount of acompound according to claim
 1. 15. The compound of claim 1 which is apharmaceutically acceptable salt.
 16. A pharmaceutical composition ofmatter comprising a compound according to claim 1 as an activeingredient.
 17. The pharmaceutical composition of matter according toclaim 16 comprising as an additional active ingredient a cytostatic orcytotoxic substance which is not a compound according to claim
 1. 18. Acompound having the following structure

or a pharmaceutically acceptable salt thereof.
 19. A compound having thefollowing structure

or a pharmaceutically acceptable salt thereof.
 20. A compound having thefollowing structure

or a pharmaceutically acceptable salt thereof.
 21. A compound having thefollowing structure

or a pharmaceutically acceptable salt thereof.
 22. A compound having thefollowing structure

or a pharmaceutically acceptable salt thereof.
 23. A compound having thefollowing structure

or a pharmaceutically acceptable salt thereof.
 24. A pharmaceuticalcomposition comprising the compound according to claim 18 as an activeingredient.
 25. A method for treating prostate cancer in a warm-bloodedanimal comprising administering to said animal a therapeuticallyeffective amount of a compound according to claim
 18. 26. Apharmaceutical composition comprising the compound according to claim 19as an active ingredient.
 27. A method for treating prostate cancer in awarm-blooded animal comprising administering to said animal atherapeutically effective amount of a compound according to claim 19.28. A pharmaceutical composition comprising the compound according toclaim 20 as an active ingredient.
 29. A method for treating prostatecancer in a warm-blooded animal comprising administering to said animala therapeutically effective amount of a compound according to claim 20.30. A pharmaceutical composition comprising the compound according toclaim 21 as an active ingredient.
 31. A method for treating prostatecancer in a warm-blooded animal comprising administering to said animala therapeutically effective amount of a compound according to claim 21.32. A pharmaceutical composition comprising the compound according toclaim 22 as an active ingredient.
 33. A method for treating prostatecancer in a warm-blooded animal comprising administering to said animala therapeutically effective amount of a compound according to claim 22.34. A pharmaceutical composition comprising the compound according toclaim 23 as an active ingredient.
 35. A method for treating prostatecancer in a warm-blooded animal comprising administering to said animala therapeutically effective amount of a compound according to claim 23.